Substituted aza and diazacycloheptane and cyclooctane compounds and their use

ABSTRACT

Aza- and diazacyclohexane and -cyclooctane compounds of the following formula: 
     
       
         Ar 1 —A—B—Ar 2   (I)  
       
     
     where Ar 1 , A, B and Ar 2  have the meanings stated in the description have a high affinity for the dopamine D 3  receptor and can therefore be used to treat disorders which respond to dopamine D 3  ligands.

This application is a 371 of PT/EP97/00106 filed Jan. 10, 1997.

The invention relates to substituted aza- and diazacycloheptane and -cyclooctane compounds and to the use of such compounds. Said compounds have valuable therapeutic properties and can be used in particular for treating disorders which respond to dopamine D₃ ligands.

Compounds of the type under discussion here and having physiological activity have in some cases been disclosed. Thus, DE 21 39 082 and DE 22 58 561 describe pyrimidine derivatives and pyrimidone derivatives with basic substituents as drugs for lowering blood pressure. These pyrimidine and pyrimidone derivatives have the formulae:

where in (A) X is, inter alia, a sulfur atom, A is a C₁-C₆-alkylene group, and R¹, R², R³ and Z are various substituents. In (B), X and Y are an oxygen or sulfur atom, A is a C₂-C₆-alkylene group, W is a vinylene group and R and Z are various substituents.

EP-A-361271 describes pyridyl and pyrimidyl derivatives of the formula:

where R₁ is halogen or hydrogen, and R₂ is halogen; X is oxygen, sulfur or methylene; R₃ and R₄, which are identical or different, are hydrogen or lower alkyl; n is 2 or 3; A is a 2-pyrimidyl group or a 2- or 3-pyridyl group, it being possible for these groups to be substituted.

These compounds can be used to treat mental disturbances.

EP-A-454498 describes compounds of the formula

where A is, inter alia, —(CH₂)_(m)— or —B—(CH₂)_(k)—, where B is O, S, an unsubstituted or substituted amino group, —CONH— or —COO—, R¹ and R² can, inter alia, together form an alkylene chain, R³ and R⁴ are a hydrogen atom or a lower alkyl group, and X¹, X² and X³ are various substituents. These compounds can be used to treat cardiac arrhythmias.

EP-A-452107 and EP-A-369627 describe structurally similar compounds which can likewise be used for treating cardiac arrhythmias.

In addition, BE-A-628 766 describes compounds of the formula

where X is a halogen atom or a lower alkyl radical, T is piperazine, methylpiperazine, homopiperazine or methylhomopiperazine; Z is alkylene or alkenylene; A is O or S; and Y is a naphthyl, halonaphthyl or an unsubstituted or mono- to trisubstituted phenyl radical. These compounds can be used to treat schistosomiasis.

Neurones obtain their information inter alia via G-protein-coupled receptors. There are numerous substances which exert their effect via these receptors. One of these is dopamine.

Confirmed information on the presence of dopamine and its physiological function as neurotransmitter is available. Cells responding to dopamine are connected with the etiology of schizophrenia and Parkinson's disease. These and other diseases are treated with drugs which interact with dopamine receptors.

Up to 1990, two subtypes of dopamine receptors had been clearly defined pharmacologically, mainly the D₁ and D₂ receptors.

More recently, a third subtype has been found, namely the D₃ receptor, which appears to mediate some of the effects of antipsychotics (J. C. Schwartz et al., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144).

D₃ receptors are mainly expressed in the limbic system. It is therefore assumed that a selective D₃ antagonist is likely to have the antipsychotic properties of the D₂ antagonists but not their neurological side effects (P. Sokoloff et al., Localization and Function of the D₃ Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

P. J. Murray et al., Bioorganic & Medicinal Chemistry Letters, Vol. 5, No. 3, 219-222 (1995), have described arylpiperazines of the formula

where R¹ and R² are H or CH₃O, and X is Br, 4-acetylphenyl, 4-methylsulfonylphenyl or 4-aminophenyl, with higher affinity and selectivity for the dopamine D₃ receptor.

We have now found, surprisingly, that certain aza- and diazacycloheptane and -cyclooctane compounds have a high affinity for the dopamine D₃ receptor and a low affinity for the D₂ receptor. They are thus selective D₃ ligands.

The present invention therefore relates to the compounds of the general formula I:

Ar¹—A—B—Ar²  (I)

where

Ar¹ is

or a 5- or 6-membered heteroaromatic ring with 1, 2 or 3 heteroatoms which are selected, independently of one another, from O, N and S, where Ar¹ may have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR¹, alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or C₂-C₆-alkenyl, C₂-C₆-alkynyl, cycloalkyl, halogen, CN, CO₂R¹, NO₂, NR¹R², SR¹, CF₃, CHF₂, phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, acyl, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl or halogen, or C₁-C₆-alkanoyl or benzoyl;

R¹ is H, alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl, phenyl or halogen;

R² has the meanings stated for R¹ or is COR¹ or CO₂R¹;

A is a C₃-C₁₅-alkylene group when Ar¹ is C₆H₅CONH, or, when Ar¹ is a 5- or 6-membered heteroaromatic ring, is a C₄-C₁₅-alkylene group or a C₃-C₁₅-alkylene group which comprises at least one group Z which is selected from O, S, NR¹, a double and a triple bond, where R¹ is as defined above,

B is a 7- or 8-membered saturated ring with one or two nitrogen heteroatoms, the nitrogen heteroatoms being located in the 1,4 or 1,5 position and the ring being bonded in position 1 to the radical A and in position 4 or 5 to the radical Ar², and it additionally being possible for the ring to have a double bond in position 3 or 4 in the monoaza ring and in position 6 in the 1,4-diaza ring;

Ar² is phenyl, pyridyl, pyrimidinyl or triazinyl, it being possible for Ar² to have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR¹, alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, alkoxyalkyl, haloalkyl, halogen, CN, CO₂R¹, NO₂, SO₂R¹, NR¹R², SO₂NR¹R², SR¹, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring with 1 to 3 heteroatoms which are selected from O, S and N, the carbocyclic or heterocyclic ring being unsubstituted or substituted by C₁-C₈-alkyl, phenyl, phenoxy, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃, where R¹ and R² have the abovementioned meanings, and Ar² may also be fused to a carbocyclic ring of the type defined above, and where Ar² cannot be a pyrimidinyl radical substituted by 2 hydroxyl groups, and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D₃ receptor ligands which intervene regioselectively in the limbic system and, because of their low affinity for the D₂ receptor, have fewer side effects than classical neuroleptics, which are D₂ receptor antagonists. The compounds can therefore be used to treat disorders which respond to dopamine D₃ receptor antagonists or agonists, eg. for treating disorders of the central nervous system, in particular schizophrenia, depression, neuroses and psychoses.

For the purpose of the present invention, the following terms have the meanings indicated thereafter:

alkyl (also in radicals such as alkoxy, alkylamino etc.) is a straight-chain or branched alkyl group with 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms and, in particular, 1 to 4 carbon atoms. The alkyl group may have one or more substituents which are selected, independently of one another, from OH and OC₁-C₈-alkyl.

Examples of an alkyl group are methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, t-butyl, etc.

Cycloalkyl is in particular C₃-C₆-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene is a straight-chain or branched radical with, preferably, 4 to 15 carbon atoms, particularly preferably 4 to 10 carbon atoms, or with 3 to 15, in particular 3 to 10, carbon atoms when the alkylene group comprises one of said groups.

The alkylene groups may comprise at least one of the groups Z indicated above in the definition of A. This may, just like the said double or triple bond, be located anywhere in the alkylene chain or in position 1 or 2 of group A (seen from the Ar¹ radical). A is particularly preferably compounds according to formula I where A is —Z—C₃-C₆-alkylene, in particular —Z—CH₂CH₂CH₂—, —Z—CH₂CH₂CH₂CH₂—, —Z—CH₂CH═CHCH₂—, —Z—CH₂C(CH₃)═CHCH₂—, —Z—CH₂C(═CH₂)CH₂—, —Z—CH₂CH(CH₃)CH₂— or a linear —Z—C₇-C₁₀-alkylene radical. In this case, A is particularly preferably —Z—C₃-C₆-alkylene when Ar¹ is an unsubstituted or substituted pyrimidine or triazole residue, and a linear —Z—C₇-C₁₀-alkylene radical when Ar¹ is an unsubstituted or substituted thiadiazole residue. In this case, Z can also be CH₂ and is preferably CH₂, O and, in particular, S.

Halogen is F, Cl, Br or I.

Haloalkyl may comprise one or more, in particular 1, 2 or 3, halogen atoms which can be located on one or more carbon atoms, preferably in the α or ω position. CF₃, CHF₂, CF₂Cl or CH₂F is particularly preferred.

Acyl is preferably HCO or C₁-C₆-alkyl-CO, in particular acetyl. If Ar¹ is substituted, the substituent can also be located on the nitrogen heteroatom.

Ar¹ is preferably compounds of the formula I where Ar¹ is

where

R³ to R⁶ are H or one of the abovementioned substituents of the Ar¹ radical,

R⁷ has the meanings indicated above for R², and

X is N or CH. When the benzamide residue is substituted, the substituents are preferably in the m or p position.

Ar¹ is particularly preferably compounds of the formula I where Ar¹ is

where R³ to R⁵, R⁷ and X have the abovementioned meanings, and in particular compounds of the formula I where Ar¹ is

where R³ to R⁵, R⁷ and X have the abovementioned meanings.

The radicals R³ to R⁶ are preferably H, C₁-C₆-alkyl, OR¹, NR¹R², SR¹, phenyl which is substituted or unsubstituted with C₁-C₆ alkyl, acyl or halogen, and halogen, where R¹ and R² have the abovementioned meanings.

The radical B is preferably

The radical Ar² may have one, two, three or four substituents, preferably one or two substituents, which are located in particular in the m position and/or p position. They are preferably selected, independently of one another, from C₁-C₆-alkyl, haloalkyl, NO₂, halogen, in particular chlorine, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, cyclopentyl and cyclohexyl. If one of the substituents is C₁-Ce-alkyl, a branched group is preferred, in particular isopropyl or t-butyl.

Ar² is preferably unsubstituted or substituted phenyl, 2-, 3- or 4-pyridinyl or 2-, 4(6)- or 5-pyrimidinyl.

If one of the substituents on the radical Ar² is a 5- or 6-membered heterocyclic ring, it is, for example, a pyrrolidine, piperidine, morpholine, piperazine, pyridine, 1,4-dihydropyridine, pyrimidine, triazine, pyrrole, thiophene, thiazole, imidazole, oxazole, isoxazole, pyrazole or thiadiazole residue, with a pyrrole, imidazole, pyrrazole or thienyl radical being preferred.

If one of the substituents on the radical Ar² is a carbocyclic radical, it is, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

If Ar² is fused to a carbocyclic radical, it is, in particular, a naphthalene, di- or tetrahydronaphthalene residue.

The invention also comprises the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung, Volume 10, pages 224 et seq., Birkhäuser Verlag, Basel and Stuttgart,1966.

The compounds of the formula I may have one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The particular tautomeric forms are also included in the invention.

The process for preparing the compounds (I) comprises

a) reacting a compound of the general formula II

Ar¹-Z—A—Y¹  (II)

where Y¹ is a conventional leaving group such as Hal, alkanesulfonyloxy, arylsulfonyloxy etc., and Z has the abovementioned meanings, with a compound of the general formula (III)

H—B—Ar²  (III)

or

b) reacting a compound of the general formula (IV)

Ar¹—A¹-Z¹H  (IV)

where Z¹ is O, NR¹ or S and A¹ is C₁-C₁₅-alkylene or a bond, with a compound of the general formula V

Y¹—A²—B—Ar²  (V)

where Y¹ has the abovementioned meaning, and A² is C₂-C₁₅-alkylene, where A¹ and A² together have 3 to 15 carbon atoms;

or

c) reacting a compound of the general formula (VI)

Ar¹-Y¹  (VI)

where Y¹ has the abovementioned meaning, with a compound of the general formula VII

H—Z¹—A—B—Ar²  (VII)

where Z¹ has the abovementioned meanings; or

d) converting a compound of the formula (VIII)

NC—A—B—Ar²  (VIII)

into a compound of the type of (IX)

and reacting the latter with a dicarbonyl compound in a conventional way; or

e) to prepare a compound of the formula I where Ar¹ is a benzamide residue:

reacting a compound of the general formula (X)

where Y² is OH, OC₁-C₄-alkyl, Cl or together with CO an activated ester group, with a compound of the formula (XI)

Z²—A²—B—Ar²  (XI)

where A² has the abovementioned meanings, and Z² is OH or NH₂.

The compounds of the formula III are starting compounds for preparing compounds of the formulae V, VII and VIII and are prepared by

a) reacting a compound of the general formula (XII)

HB¹  (XII)

where B¹ is

with a compound of the general formula (XIII)

Y¹—Ar²  (XIII)

where Y¹ is one of the abovementioned leaving groups and Ar² has the abovementioned meaning, in a conventional way; or

b) reacting a compound of the general formula (XIV)

H—B²

where B² is

with n=1 or 2,

with a compound of the general formula (XV)

Y²—Ar²

where Y² is Br, Cl or I, and Ar² has the above meanings, by known processes as described, for example, by S. C. Buchwald et al., Angew. Chem. 1995, 107, 1456 or J. F. Hartweg et al., Tetrahedron Lett 1995, 36, 3604 and J. K. Stille et al., Angew. Chem. 1986, 98, 504 or Pereyre M. et al., in Organic Synthesis, Butterworth 1987; or

c) reacting a compound of the general formula (XVI)

where n=1 or 2,

with a compound M—Ar² where M is a metal such as Li or MgY². MAr² can be obtained from compounds of the formula XV by methods known from the literature.

Compounds of the type of Ar¹ and Ar² are either known or can be prepared by known processes as described, for example, in A. R. Katritzky, C W. Rees (ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press, or “The Chemistry of Heterocyclic Compounds”, J. Wiley & Sons Inc. NY and the literature cited therein.

Compounds of type B are either known or can be prepared by processes similar to known ones, for example

1,4- and 1,5-diazacycloalkanes: L. Börjeson et al. Acta Chem. Scand. 1991, 45, 621 Majahrzah et al Acta Pol. Pharm., 1975, 32, 145

1,4-diazacyclooct-6-enes: W. Schroth et al. Z. Chem. 1969, 9, 143

1-azacyclooctanones: N. J. Leonard et al. J. Org. Chem. 1964, 34, 1066

1-azacyclo-heptanones: A. Yokoo et al. Bull Chem. Soc. Jpn. 1956, 29, 631

The novel compounds and the starting materials and intermediates can also be prepared by methods similar to those described in the patent publications mentioned at the outset.

The reactions described above generally take place in a solvent at temperatures between room temperature and the boiling point of the solvent used. Solvents which can be used are, for example, ethyl acetate, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, a ketone such as acetone or methyl ethyl ketone, or an alcohol such as ethanol or butanol.

An acid-binding agent is present if required. Suitable acid-binding agents are inorganic bases such as sodium or potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride or organometallic compounds such as butyllithium or alkylmagnesium compounds, or organic bases such as triethylamine or pyridine. The latter can also act as solvent.

The reactions take place where appropriate with use of a catalyst such as transition metals or complexes thereof, eg. Pd(PPh₃)₄, Pd(OAc)₂ or Pd(P(oTol)₃)₄, or of a phase-transfer catalyst, eg. tetrabutylammonium chloride or tetrapropylammonium bromide.

The crude product is isolated in a conventional way, for example by filtration, removal of the solvent by distillation, or extraction from the reaction mixture etc. The resulting compounds can be purified in a conventional way, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.

The acid addition salts are prepared in a conventional way by mixing the free base with the appropriate acid, where appropriate in solution in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, an ether such as methyl t-butyl ether, a ketone such as acetone or methyl ethyl ketone, or an ester such as ethyl acetate.

To treat the abovementioned disorders, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active substance is about 10 to 1000 mg per patient and day on oral administration and about 1 to 500 mg per patient and day on parenteral administration.

The invention also relates to pharmaceutical compositions which comprise the compounds according to the invention. These compositions are in the form of the conventional solid or liquid pharmaceutical presentations, for example as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions or sprays. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart,1978). The presentations obtained in this way normally contain from 1 to 99% by weight of active substance.

The following examples serve to illustrate the invention without limiting it.

EXAMPLE 1

1-[2-t-Butyl-6-trifluoromethyl-pyrimidin-4-yl]-4-[3-[4-hydroxy-pyrimidin-2-ylmercapto)-propyl]-hexahydro-(1H))-1,4-diazepine fumarate

Preparation of the starting materials:

a) 2-t-Butyl-4-hydroxy-6-trifluoromethylpyrimidine.

The above pyridimine was synthesized in a conventional way by condensing 2,2-dimethylpropionamidine with ethyl trifluoroacetoacetate and sodium ethoxide in ethanol, see

Heterocyclic Compounds, Vol. 52, The Pyrimidines, page 189 et seq., D. J. Brown et al. (Eds.) John Wiley and Sons, 1994.

Melting point 187-188° C.

The 4-hydroxypyrimidines of the formula

were obtained in a similar way.

R M.p. [° C.] t-C₄H₉ 169 n-C₃H₇ 120 CF₂Cl 135-136

b) 2-t-Butyl-4-chloro-6-trifluoromethylpyrimidine The hydroxypyrimidine from stage a) was converted with phosphorus oxychloride or thionyl chloride in a conventional way into the chlorine compound, see Heterocyclic Compounds, Vol. 52, The pyrimidines, page 329 et seq., John Wiley and Sons, 1994. The compound is in the form of a yellowish oil.

The 4-chloropyrimidines of the formula

were obtained in a similar way:

R M.p. [° C.] t-C₄H₉ oil n-C₃H₇ oil CF₂Cl oil

c) 1-[2-t-Butyl-6-trifluoromethylpyrimidin-4-yl]hexahydro-(1H))-, 1,4-diazepine

18 g (0.18 mol) of homopiperazine were dissolved in 25 ml of ethanol and, while refluxing, a solution of 7.2 g (0.03 mol) of the chloride obtained in b), dissolved in 10 ml of ethanol, was added dropwise over the course of 1 h. After reacting for a further 30 min, the cooled mixture was worked up by adding 200 ml of water and extracting several times with a total of 200 ml of methylene chloride. The organic phase was then washed with water, dried with anhydrous sodium sulfate and concentrated. The required compound was obtained as a yellowish oil which was further processed unpurified. Yield: 98% of theory.

The following compounds were obtained in a corresponding way: 1-aryl-1,4-diazepine of the formula:

Ar² M.p. [° C.]

Oil

Oil

Oil

74-75

d) 1-[2-t-Butyl-6-trifluoromethylpyrimidin-4-yl]-4-(3-chloropropyl)hexahydro-(1H))-1,4-diazepine

5 g (0.0165 mol) of the compound obtained above under c) were refluxed together with 2.5 g (0.025 mol) of triethylamine and 3.15 g (0.02 mol) of 1-bromo-3-chloropropane in 50 ml of tetrahydrofuran for 10 h. The solvent was then removed by distillation, and the residue was washed with water and extracted with methylene chloride. The residue obtained after drying and concentrating was then purified by flash chromatography (silica gel).

Yield: 4.8 g (77% of theory) of yellow oil

The compounds listed below were obtained in a similar manner:

1-aryl-4-haloalkyl-1,4-diazepines of the formula

Hal alk Ar² M.p. [° C.] Cl

Oil ″

″ Oil ″ —(CH₂)₃—

Oil ″ ″

Oil ″ ″

Oil ″

Oil ″ —(CH₂)₃—

Oil ″ ″

Oil

Preparation of the final product

5 g (0.013 mol) of the product obtained in d) were dissolved in 25 ml of dimethylformamide and added dropwise to a stirred solution at 100° C. of 2.03 g (0.016 mol) of 2-thiouracil, 0.38 g (0.016 mol) of lithium hydroxide and 1 g of sodium iodide in 50 ml of dimethylformamide over the course of 1 h. After reaction for 3 hours, the solvent was removed by distillation under reduced pressure, and the residue was mixed with 150 ml of water and extracted twice with ethyl acetate. The residue obtained after washing with water, drying with sodium sulfate and concentrating was purified by chromatography. (Flash chromatography, silica gel, mobile phase methylene chloride with 2.5-5% methanol)

Yield: 4 g of pale oil

NMR:CDCl₃.δ 1.3(s,9H); 1.85-2.25(m,4H); 2.6(m,4H); 2.8(m,2H); 3.2(t,2H); 3.5(m,2H); 4.0(m,2H); 6.2(d,1H); 6.5(s,1H); 7.8(d;1H)

The substance was obtained as fumarate by adding an ethanolic solution of fumaric acid.

C₂₁H₂₉F₃N₆OS.C₄H₄O₄ MW 586.6

Melting point: 188-189° C.

The compounds listed in the following Table 1 were obtained in a similar way using various haloalkyl-1,4-diazepines (eg. 1d) and various mercapto-substituted heterocycles such as thiouracil, 5-amino-2-mercaptotriazoles and 5-amino-2-mercaptothiadiazole:

TABLE 1

Ex. No. Ar¹ alk Ar² M.p. [° C.] 2

—(CH₂)₃—

155-162 Oxalate 3 ″ ″

83-85 Oxalate 4 ″ ″

177-182 Fumarate 5 ″ ″

72-74 6 ″

116-119 7 ″

174-180 Oxalate 8 ″ ″

60-70 Oxalate 9

—(CH₂)₃—

166-167 Fumarate 10 ″ ″

55-60 11 ″ ″

110-115 Oxalate 12 ″ ″

136-140 Hydrochloride 13 ″ ″

95-98 14

″

142-144 15

125-128 16 ″

113-119 Oxalate 17 ″ ″

230-232 Hydrochloride 18

—(CH₂)₃—

Oil 19 ″ ″

109-110 20 ″ ″

60-67 21 ″

″ 180-190 Hydrochloride 22 ″

″ 119-122 23 ″

92-97 Oxalate

EXAMPLE 24

1-(4-Bromobenzamido)-4-[4-(2,6-bis-t-butyl-4-pyrimidinyl)hexahydro-(1H)-1,4-diazepin-1-yl]butane

Preparation of the starting materials

a) Hexahydro-1-[2-t-butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-phthalimidobutyl)-(1H)-1,4-diazepine

10 g (0.033 mol) of the diazepine prepared in Example 1c) were refluxed with 9.8 g (0.035 mol) of N-(4-bromobutyl)phthalimide and 9.1 g (0.066 mol) of potassium carbonate in 120 ml of acetonitrile for 8 h. The mixture was filtered and the filtrate was concentrated. The residue was processed further unpurified.

Yield: 16.2 g (98% of theory)

A sample was recrystallized from ethanol.

Melting point 97-99° C.

The following were obtained in a similar way:

alk Ar² M.p. [° C.] —(CH₂)₃—

89-92

″ 130-132 —(CH₂)₃—

119-121 —(CH₂)₄— ″ 207-209 —(CH₂)₄—

190-192 b) Hexahydro-1H-1-[2-t-butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-aminobutyl)-1,4-diazepine

15 g (0.03 mol) of the product described above under a) were refluxed with 6 g of hydrazine hydrate in 200 ml of ethanol for 2 h, and then the precipitate was filtered off with suction and the filtrate was evaporated. The residue was taken up in ethyl acetate, filtered again, washed with water, dried and again evaporated.

9.2 g (83% of theory) were obtained as an oil.

The following were obtained in a similar way:

alk Ar² M.p. [° C.] —(CH₂)₄—

Oil —(CH₂)₃— ″ Oil —(CH₂)₄—

Oil —(CH₂)₃—

Di-Hydrochloride: 241-245

Preparation of the final products:

3 g (0.0083 mol) of the product obtained above under b) were dissolved with 0.9 g (0.009 mol) of triethylamine in 60 ml of tetrahydrofuran, and a solution of 2 g (0.009 mol) of 4-bromobenzoyl chloride in 10 ml of tetrahydrofuran was added dropwise at room temperature over the course of 10 min. After 1 h, the solvent was removed by distillation under reduced pressure, and the residue was mixed with water and extracted twice with methylene chloride. The dried and concentrated solvent phase was purified by flash chromatography (silica gel, mobile phase methylene chloride with 3% methanol).

Yield: 4.2 g (93% of theory)

Melting point 125-127° C. (from diisopropyl ether/isopropanol) C₂₈H₄₂BrN₅O (544.6)

The compounds listed in Table 2 below were obtained using various amino derivatives (similar to 24b) and known benzoyl chlorides.

TABLE 2

Ex. M.p. No. R n Ar² [° C.] 25 Br 3 ″ 169-171 26 ″ 4

74-76 Oxalate 27 t-Butyl 4

165-167 Oxalate 28

4 ″ 104-107 Oxalate 29 Br 4

92-94 Oxalate 30 I 4 ″ 110-115 Oxalate

EXAMPLE 31

4-[4-{4-Benzyloxy-2-pyrimidinylamino}butyl]-1-[2-t-butyl-6-trifluoromethyl-4-pyrimidinyl]hexahydro-1H-1,4-diazepine oxalate

2.7 g (0.007 mol) of the amino compound prepared in Example 24b) were introduced with 0.3 g of sodium hydride (0.009 mol) into 20 ml of dimethylformamide. After reaction for 1 h, 1.6 g (0.006 mol) of 4-benzyloxy-2-methylsulfonylpyrimidine (prepared by oxidizing 4-benzyloxy-2-methylmercaptopyrimidine), dissolved in 10 ml of dimethylformamide, were added, and the mixture was stirred at room temperature for 72 h.

Subsequently, water was added, the mixture was extracted with ethyl acetate, and the solution was dried and concentrated. The residue was purified by column chromatography (silica gel, methylene chloride with 4% methanol)

Pure yield: 1.0 g (30% of theory)

Oxalate: Melting point 145-150° C. C₂₉H₃₈F₃N₇O.C₂H₂O₄ (647.7)

EXAMPLE 32

1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-[4-{4-hydroxy-2-pyrimidinylamino}butyl]hexahydro-(1H))-1,4-diazepine

0.7 g (0.001 mol) of the compound described in the previous example was hydrogenated in methanol with palladium on carbon catalyst (10% Pd) under normal conditions.

Yield: 0.6 g (100% of theory)

Melting point 111-115° C. C₂₂H₃₂F₃N₇O.C₂H₄O₄ (557.5)

EXAMPLE 33

1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-[4-(4-hydroxy-2-pyrimidinyl)butyl]hexahydro-1H-1,4-diazepine

a) 1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-cyanobutyl)hexahydro-1,4-diazepine

9.1 g (0.03 mol) of the diazepine from Example 1c) were dissolved with 3.5 g (0.03 mol) of 5-chlorovaleronitrile and 9.1 g of triethylamine (0.09 mol) in 100 ml of dimethylformamide and heated at 100° C. for 24 h.

The solvent was then removed by distillation under reduced pressure, water was added, the mixture was extracted with ethyl acetate, and this phase was dried with sodium sulfate and concentrated. The residue was processed further unpurified.

Yield: 9.1 g as brown oil

b) 1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-(4-amidino-butyl)hexahydro-1,4-diazepine hydrochloride

9.1 g (0.024 mol) of the nitrile described above were dissolved in 2 ml of ethanol and 50 ml of methylene chloride (both anhydrous) and, while cooling to 0-10° C., dry hydrogen chloride gas was passed in to saturation. After stirring overnight, the precipitate was filtered off with suction and the filtrate was concentrated.

Yield: 7.6 g (58% of theory)

Preparation of the final product

4.4 g (0.01 mol) of the amidine described above were stirred with the sodium compound of ethyl formylacetate (preparation J. Org. Chem. 35 (1970), 2515 et seq.) (2.8 g (0.02 mol)) in 50 ml of water and 20 ml of tetrahydrofuran overnight. The reaction mixture was then extracted several times with ethyl acetate, and the organic phase was dried and concentrated. The residue was purified by column chromatography (silica gel, eluent methylene chloride with 4% methanol)

Yield: 1.9 g (42%) of oil

NMR: (CDCl₃) δ: 1.3(s,9H); 1.8-2.0(m,4H); 2.0(m,2H); 2.4-2.6(m/br,6H); 2.5(t,2H); 3.5(m,1H); 4.0(m,2H); 6.2(d,1H); 6.5(s,1H); 7.8(d,1H) C₂₂H₃₁F₃N₆O (425.5)

Oxalate: C₂₂H₃₁F₃N₆O.C₂H₂O₄ (542.5)

Melting point 173-177° C. (decomposition)

EXAMPLE 34

1-[2-t-Butyl-6-trifluoromethyl-4-pyrimidinyl]-4-[3-{4-benzyloxy-2-pyrimidinyloxy}propyl]hexahydro-(1H))-1,4-diazepine

a) Starting material

8.9 g (64.5 mmol) of 3-bromo-1-propanol were taken up in 50 ml of abs. THF, and 6.52 g (64.5 mmol) of triethylamine, a catalytic amount of sodium iodide and 16.2 g (53.7 mmol) of the azepine prepared in Example 1c) were successively added, and the mixture was refluxed for 16 h. For workup, the precipitate salts were filtered off and the mother liquor was concentrated under reduced pressure. The resulting oil was taken up in dichloromethane, and the organic phase was washed with water, dried over sodium sulfate and then purified by column chromatography (SiO₂, mobile phase CH₂Cl₂:MeOH=98:2) to result in a colorless oil.

Yield: 10.11 g (53%)

b) Final product

0.26 g (8.52 mmol) of sodium hydride (80%) was added in portions to 2.45 g of the product described above, dissolved in 25 ml of abs. DMF, at room temperature under a protective gas atmosphere, and the mixture was stirred for 30 min. Then 1.5 g (5.68 mmol) of 2-methanesulfonyl-4-benzyloxypyrimidine (prepared by methods similar to the literature: W. E. Barnett, R. F. Koebel Tetrahedron Lett. 1971, 20, 2867) dissolved in 15 ml of abs. DMF, were added dropwise. After 7 h, the mixture was worked up by pouring into water and extracting with tert-butyl methyl ether. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was purified by column chromatography (SiO₂, mobile phase CH₂Cl₂:MeOH=98:2) to afford the substance as an oil.

Yield: 1.6 g (2.9 mmol, 52%)

To form the hydrochloride, the oil was dissolved in ethyl acetate/Et₂O, ethereal hydrochloric acid was added under protective gas, and the resulting salt was filtered off with suction.

Melting point: 110-112° C. C₂₈H₃₆ClF₃N₆O₂ (581.1)

EXAMPLE 35

1-[2-t-Butyl-6-trifluoromethyl-2-pyrimidinyl]-4-[3-(4-hydroxy-2-pyrimidinyloxy)propyl]hexahydro-(1H)-1,4-diazepine

1.4 g (2.6 mmol) of the substance from Example 34, dissolved in 40 ml of ethyl acetate, were mixed at room temperature with 0.2 g of Pd/C (10% Pd) and hydrogenated with hydrogen at 40-50° C. under atmospheric pressure. After the reaction was complete, the catalyst was filtered off with suction and, after washing with ethyl acetate, the filtrated was concentrated under reduced pressure.

Yield: 1.2 g (100%)

To form the hydrochloride, the oil was dissolved in ethyl acetate/Et₂O, ethereal hydrochloric acid was added under protective gas, and the resulting salt was filtered off with suction.

Melting point: 78-80° C. C₂₁H₃₀ClF₃N₆O₂ (491)

The compounds mentioned in the following Tables 3 to 17 are obtained in a similar way.

TABLE 3

Example No. R1 R2 R3 R6 R7 R8 R9 R10 W X—Y—Z A B 36 H H OH H tBut H Me H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 37 H H OH H tBut H Ph H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₃— 38 Me H OH H tBut H 1-Pyrrolyl H CH₂ CH═C—CH₂ S —(CH₂)₃— 39 H H NH₂ H iProp H 2-Napht H CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 40 H Me OH H Et H tBut H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 41 H H OH H CHF₂ H H H CH₂ CH₂—CH═C S —(CH₂)₃— 42 H H NH₂ OMe CF₃ H H H CH₂ CH═C—CH₂ S —(CH₂)₃— 43 H H OH H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 44 H H NHMe H iProp H H H CH₂ CH₂—N—CH₂ O —(CH₂)₄— 45 Me H OH H H CN tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 46 H H OH H H F tBut H CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 47 H Me NH₂ H H Cl iProp H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 48 H H NHMe H tBut H H OMe CH₂ CH₂—CH═C S —(CH₂)₃— 49 H H OH H iProp H H OMe CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₄— 50 H H OH H CHF₂ H tBut H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₃— 51 H H OH OMe tBut H CF₃ H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 52 Me H OH H CF₃ H tBut H CH₂ CH₂—N—CH₂ O —(CH₂)₅— 53 H H NH₂ H nProp CN tBut H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 54 H Me OH H CF₃ CN iProp H CH₂ CH═C—CH₂ S —(CH₂)₃— 55 H H OH H Ph C≡CH tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 56 H H NH₂ H tBut CN H H CH₂ CH₂—CH═C S —(CH₂)₃— 57 H H NHMe H tBut CN CF₃ OMe CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₅— 58 H H OH OMe nProp F tBut H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₄— 59 H H OH H Ph CN tBut Me CH₂ CH₂—CH═C S —(CH₂)₃— 60 H H OH OMe tBut F H H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 61 H H OH H tBut H Me H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 62 H H OH H tBut H Ph H CH₂ CH₂—CH═C S —CH₂—C(═CH₂)—CH₂— 63 Me H OH H tBut H 1-Pyrrolyl H CH₂—CH₂ CH═C—CH₂ S —CH₂—C(═CH₂)—CH₂— 64 H H NH₂ H iProp H 2-Napht H CH₂—CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂— 65 H Me OH H Et H tBut H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 66 H H OH H CHF₂ H H H CH₂—CH₂ CH═C—CH₂ S —CH₂—C(═CH₂)—CH₂— 67 H H NH₂ OMe CF₃ H H H CH₂ CH₂—CH═C S —CH₂—CH(CH₃)—CH₂— 68 H H OH H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 69 H H NHMe H iProp H H H CH₂ CH₂—N—CH₂ O —CH₂—C(═CH₂)—CH₂— 70 Me H OH H H CN tBut H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH═CH—CH₂— 71 H H OH H H F tBut H CH₂—CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂— 72 H Me NH₂ H H Cl iProp H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 73 H H NHMe H tBut H H OMe CH₂ CH₂—CH═C S —CH₂—CH(CH₃)—CH₂— 74 H H OH H iProp H H OMe CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 75 H H OH H CHF₂ H tBut H CH₂—CH₂ CH₂—CH═C S —CH₂—C(═CH₂)—CH₂— 76 H H OH OMe tBut H CF₃ H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH═CH—CH₂— 77 Me H OH OMe CF₃ H tBut H CH₂ CH₂—N—CH₂ O —CH₂—C(═CH₂)—CH₂— 78 H H NH₂ H nProp CN tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 79 H Me OH H CF₃ CN iProp H CH₂ CH₂—CH═C S —CH₂—CH(CH₃)—CH₂— 80 H H OH H Ph C≡CH tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 81 H H NH₂ H tBut CN H H CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂— 82 H H NHMe H tBut CN CF₃ OMe CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH═CH—CH₂— 83 H H OH H nProp F tBut H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 84 H H OH H Ph CN tBut Me CH₂—CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂— 85 H H OH H tBut F H H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂—

TABLE 4

Example No. R1 R2 R3 R7 R9 R10 W X—Y—Z A B 86 H H OH tBut Ph H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 87 H H OH tBut 2-Napht H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 88 Me H OH tBut 1-Pyrrolyl H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 89 H H NH₂ tBut cHex H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 90 H H OH tBut nHex H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 91 H H OH tBut H OMe CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 92 H Me OH iProp F H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—CH═CH—CH₂— 93 H H NH₂ CH₃ 1-Pyrrolyl H CH₂ CH₂—C═CH NH —(CH₂)₃— 94 H H OH OMe 1-Pyrrolyl H CH₂ CH₂—N—CH₂ O —CH₂—CH(CH₃)—CH₂— 95 H H OH tBut H CH₃ CH₂—CH₂ CH═C—CH₂ S —CH₂—CH(CH₃)—CH₂— 96 H H OH tBut tBut OMe CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 97 Me H OH tBut iProp H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 98 H H NH₂ Ph tBut Cl CH₂ CH₂—C═CH —CH₂— —CH₂—C(CH₃)═CH—CH₂— 99 H H OH 2-Napht tBut Me CH₂—CH₂ CH═C—CH₂ S —(CH₂)₃— 100  H H OH tBut CF₃ Me CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂—

TABLE 5

Example No. R1 R2 R3 R7 R8 R9 R10 W X—Y—Z A B 101 H H OH tBut H tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 102 H H OH tBut CN H H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 103 Me H OH tBut H Cl H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 104 H H OH H CN tBu H CH₂—CH₂ CH₂—CH═C —CH₂— —CH₂—CH(CH₃)—CH₂— 105 H H NH₂ CF₃ H tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 106 H H OH nProp H iProp H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂₁—CH(CH₃)—CH₂— 107 H me OH H H iProp OMe CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 108 H H OH tBut H tBut H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 109 H H OH tBut CN H H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 110 H H NH₂ tBut H Cl H CH₂ CH₂—N—CH₂ O —(CH₂)₃— 111 Me H OH H CN tBu H CH₂ CH═C—CH₂ S —CH₂—C(CH₃)═CH—CH₂— 112 H H OH CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 113 H H OH nProp H iProp H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 114 H H NHMe H H iProp OMe CH₂ CH₂—N—CH₂ S —(CH₂)₃— 115 H H OH nProp CN tBut H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 116 H H OH CF₃ CN iProp H CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 117 Me H OH Ph C═CH tBut H CH₂ CH₂—N—CH₂ NH —CH₂—CH(CH₃)—CH₂— 118 H H OH tBut CN tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 119 H H NH₂ tBut H nProp H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 120 H H OH Ph H tBut OMe CH₂ CH₂—CH═C —CH₂— —(CH₂)₅— 121 H Me OH CF₃ H tBut F CH₂—CH₂ CH═C—CH₂ S —CH₂—CH(CH₃)—CH₂— 122 H H OH tBut F H Me CH₂ CH₂—N—CH₂ NH —CH₂—CH═CH—CH₂— 123 H H OH nProp CN tBut Me CH₂—CH₂ CH₂—CH═C S —CH₂—C(═CH₂)—CH₂— 124 H H NH₂ nProp C═CH tBut H CH₂ CH═C—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 125 H H OH tBut CN H Me CH₂ CH₂—N—CH₂ S —(CH₂)₄—

TABLE 6

Example No. R1 R2 R3 R6 R8 R9 R10 W X—Y—Z A B 126 H H OH OMe H tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 127 H H OH OMe H CF₃ H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 128 Me H OH OMe H tBut H CH₂—CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 129 H H OH H CN tBut H CH₂ CH═C—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 130 H H NH₂ H F tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 131 H H OH Me Cl iProp H CH₂ CH₂—CH═C —CH₂— —CH₂—C(═CH₂)—CH₂— 132 H Me OH H H iProp H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₃— 133 H H OH H H tBut OMe CH₂—CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 134 H H OH CN H CF₃ H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 135 H H NH₂ H CN H OMe CH{hd 2 CH₂—N—CH₂ O —CH₂—CH(CH₃)—CH₂— 136 Me H OH H H tBu F CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂— 137 H H OH H CN tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 138 H H OH Me H iProp H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 139 H H NHMe OMe H iProp H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—CH(CH₃)—CH₂— 140 H H OH OMe CN tBut H CH₂ CH═C—CH₂ S —(CH₂)₃— 141 H H OH OMe Me tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 142 Me H OH H CN tBut H CH₂—CH₂ CH₂—N—CH₂ NH —CH₂—CH═CH—CH₂— 143 H H OH Me H tBut H CH₂ CH₂—CH═C —CH₂— —CH₂—C(═CH₂)—CH₂— 144 H H NH₂ H Cl CF₃ Me CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 145 H H OH OMe CN tBut Me CH₂ CH═C—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 146 H me OH Me Me iProp Me CH₂ CH₂—CH═C S —(CH₂)₃—

TABLE 7

Example No. R1 R2 R3 R6 R7 R9 R10 W X—Y—Z A B 147 H H OH H tBut tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 148 H H OH H tBut Ph H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 149 Me H OH H tBut 1-Pyrrolyl H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 150 H H OH H nPropyl tBut H CH₂—CH₂ CH₂—CH═C —CH₂— —CH₂—C(CH₃)═CH—CH₂— 151 H H NH₂ H CF₃ tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 152 H H OH H 2-Napht tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 153 H Me OH OMe tBut H H CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 154 H H OH OMe iProp H H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 155 H H OH OMe H CF₃ H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 156 H H NH₂ H tBut H H CH₂ CH₂—N—CH₂ O —CH₂—CH(CH₃)—CH₂— 157 Me H OH H iProp H Me CH₂ CH═C—CH₂ S —CH₂—C(CH₃)═CH—CH₂— 158 H H OH CN tBut H H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 159 H H OH H H CF₃ Me CH₂ CH₂—N—CH₂ S —(CH₂)₃— 160 H H NHMe H nProp tBut H CH₂ CH₂—N—CH₂ S —CH₂—CH(CH₃)—CH₂— 161 H H OH OMe tBut iProp H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 162 H H OH OMe CF₃ tBut H CH₂—CH₂ CH═C—CH₂ NH —(CH₂)₃— 163 Me H OH Me tBut nProp H CH₂ CH₂—CH═C —CH₂— —CH₂—CH═CH—CH₂— 164 H H OH Me tBut H H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—(═CH₂)—CH₂— 165 H H NH₂ H tBut tBut H CH₂ CH═C—CH₂ —CH₂— —(CH₂)₃— 166 H H OH Me CF₃ tBut H CH₂ CH₂—CH═C S —CH₂—CH(CH₃)—CH₂—

TABLE 8

Exam- ple No. Q R2 R5 R6 R7 R8 R9 W X—Y—Z A B 167 NCH₃ NH₂ H tBut H Me H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 168 S NH₂ H tBut H Ph H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 169 NCH₃ NH₂ H tBut H 1-PYrrolyl H CH₂—CH₂ CH₂—N—CH₂ NH —(CH₂)₃— 170 NCH₃ NH₂ H iProp H 2-Napht H CH₂ CH₂—CH═C —CH₂— —(CH₂)₃— 171 S NH₂ H Et H tBut H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 172 S NH₂ H CHF₂ H H H CH₂ CH═C—CH₂ —CH₂— —(CH₂)₈— 173 NCH₃ NH₂ H CHF₂ H tBut H CH₂ CH₂—CH═C S —(CH₂)₁₀— 174 NCH₃ NH₂ H CF₃ H tBut H CH₂ CH₂—N—CH₂ NH —(CH₂)₃— 175 NCH₃ NH₂ H iProp F H H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 176 NCH₃ NH₂ H H CN tBut H CH₂ CH₂—CH═C O —(CH₂)₃— 177 S NH₂ H H F tBut H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₃— 178 NCH₃ NH₂ H H Cl iProp H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 179 NCH₃ NH₂ H tBut H H OMe CH₂ CH═C—CH₂ S —(CH₂)₃— 180 S NH₂ H nProp CN tBut H CH₂—CH₂ CH₂—CH═C —CH₂— —(CH₂)₃— 181 NCH₃ NH₂ H CF₃ CN iProp H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 182 NCH₃ NH₂ H Ph C═CH tBut H CH₂ CH═C—CH₂ —CH₂— —(CH₂)₃— 183 NCH₃ NH₂ OMe tBut CN H H CH₂ CH₂—CH═C S —(CH₂)₃— 184 NCH₃ NH₂ OMe tBut CN H H CH₂ CH₂—CH═C S —(CH₂)₃— 185 S NH₂ H tBut CN CF₃ OMe CH₂—CH₂ CH₂—N—CH₂ NH —(CH₂)₃— 186 NCH₃ NH₂ Me tBut F H H CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 187 S NH₂ H iProp H H OMe CH₂ CH₂—N—CH₂ S —(CH₂)₃— 188 N(iProp) NH₂ H tBut H Me H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 189 N(iProp) NH₂ H tBut H Ph H CH₂—CH₂ CH₂—N—CH₂ NH —(CH₂)₄— 190 S NH₂ H tBut H 1-Pyrrolyl H CH₂ CH═C—CH₂ S —(CH₂)₃— 191 N(iProp) NH₂ H iProp H 2-Napht H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 192 S NH₂ H Et H tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₁₀— 193 N(iProp) NH₂ H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₄— 194 N(iProp) NH₂ H H CN tBut H CH₂—CH₂ CH═C—CH₂ NH —(CH₂)₃— 195 N(iProp) NH₂ H H F tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 196 N(iProp) NH₂ H H Cl iProp H CH₂ CH═C—CH₂ —CH₂— —(CH₂)₃— 197 S NH₂ H tBut H H OMe CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₈— 198 N(iProp) NH₂ H nProp CN tBut H CH₂ CH₂—CH═C —CH₂— —(CH₂)₃— 199 S NH₂ H CF₃ CN iProp H CH₂ CH₂—N—CH₂ S —(CH₂)₄— 200 N(iProp) NH₂ H Ph C═CH tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —(CH₂)₃— 201 N(iProp) NH₂ H tBut CN CF₃ OMe CH₂ CH₂—N—CH₂ NH —(CH₂)₃— 202 N(iProp) NH₂ H Ph CN tBut Me CH₂—CH₂ CH₂—N—CH₂ O —(CH₂)₃— 203 S NH₂ H iProp H H OMe CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₈— 204 N(iProp) NHMe H tBut H Me H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 205 N(iProp) NHMe H tBut H Ph H CH₂ CH₂—CH═C —CH₂— —CH₂—C(═CH₂)—CH₂— 206 S NHMe H tBut H 1-Pyrrolyl H CH₂—CH₂ CH═C—CH₂ S —CH₂—CH═CH—CH₂— 207 N(iProp) NHMe H iProp H 2-Napht H CH₂ CH₂—N—CH₂ NH —CH₂—CH(CH₃)—CH₂— 208 N(iProp) NHMe H Et H tBut H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—CH(CH₃)—CH₂— 209 N(iProp) OH H tBut H Cl H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 210 N(iProp) OH H CF₃ H Cl H CH₂ CH═C—CH₂ NH —CH₂—CH(CH₃)—CH₂— 211 N(iProp) OH H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 212 S OH H iProp CN F H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 213 N(iProp) OMe H H CN tBut H CH₂ CH₂—CH═C —CH₂— —CH₂—C(═CH₂)—CH₂— 214 N(iProp) OMe H H F tBut H CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂— 215 S OMe H H Cl iProp H CH₂ CH═C—CH₂ O —CH₂—CH(CH₃)—CH₂— 216 N(iProp) OMe H tBut H H OMe CH₂—CH₂ CH═C—CH₂ NH —CH₂—C(CH₃)═CH—CH₂— 217 N(iProp) NHMe H nProp CN tBut H CH₂ CH₂—N—CH₂ NH —CH₂—CH(CH₃)—CH₂— 218 S NHMe H CF₃ CN iProp H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—C(CH₃)═CH—CH₂— 219 N(iProp) OH H Ph C═CH tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 220 N(iProp) OH OMe tBut CN H H CH₂ CH₂—CH═C NH —CH₂—CH(CH₃)—CH₂— 221 N(iProp) OH H tBut CN CF₃ OMe CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 222 S OH H nProp F tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 223 S OMe H Ph CN tBut Me CH₂ CH₂—CH═C —CH₂— —CH₂—C(═CH₂)—CH₂— 224 N(iProp) OMe OMe tBut F H H CH₂ CH═C—CH₂ S —CH₂—CH(CH₃)—CH₂— 225 N(iProp) OMe H iProp H H OMe CH₂ CH₂—CH═C S —CH₂—C(CH₃)═CH—CH₂—

TABLE 9

Example No. Q R2 R6 R8 R9 W X—Y—Z A B 226 NCH₃ NH₂ tBut Ph H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 227 NCH₃ NH₂ tBut 2-Napht H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 228 NCH₃ NH₂ tBut 1-Pyrrolyl H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 229 NCH₃ NHMe tBut cHex H CH₂—CH₂ CH₂—CH═C —CH₂— —(CH₂)₃— 230 NCH₃ NH₂ tBut nHex H CH₂ CH₂—N—CH₂ S —(CH₂)₅— 231 S NH₂ tBut Ph H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₈— 232 S NHMe iProp 1-Pyrrolyl H CH₂ CH₂—N—CH₂ S —CH₂—CH(CH₃)—CH₂— 233 S NH₂ CH₃ CH₃ H CH₂—CH₂ CH₂—CH═C NH —(CH₂)₃— 234 NCH₃ NH₂ H CHF₂ H CH₂ CH₂—N—CH₂ O —CH₂—C(═CH₂)—CH₂— 235 S NH₂ tBut tBut H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₁₀— 236 S NHMe tBut iProp H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—C(CH₃)═CH—CH₂— 237 NCH₃ NH₂ tBut tBut H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 238 NCH₃ NH₂ 2-Napht tBut Me CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 239 S NH₂ tBut CF₃ H CH₂—CH₂ CH₂—CH═C S —(CH₂)₈— 240 NCH₃ NH₂ tBut H CH₃ CH₂ CH₂—N—CH₂ S —(CH₂)₃— 241 N(iProp) NH₂ tBut Ph H CH₂—CH₂ CH═C—CH₂ S —CH₂—(═CH₂)—CH₂— 242 N(iProp) NH₂ tBut 2-Napht H CH₂ CH₂—CH═C NH —(CH₂)₃— 243 N(iProp) NH₂ tBut 1-Pyrrolyl H CH₂ CH₂—N—CH₂ O —CH₂—CH(CH₃)—CH₂— 244 N(iProp) NH₂ tBut cHex H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 245 S NH₂ tBut tBut H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 246 S OH tBut F H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₁₀— 247 N(nProp) OMe iProp tBut H CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH═CH—CH₂— 248 N(nProp) OMe CH₃ 1-Pyrrolyl H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 249 N(nProp) NCH₂Ph H iProp H CH₂—CH₂ CH₂—N—CH₂ S —CH₂—CH═CH—CH₂— 250 N(iProp) OH tBut tBut H CH₂ CH═C—CH₂ —CH₂— —(CH₂)₄— 251 N(iProp) OH tBut iProp F CH₂—CH₂ CH₂—N—CH₂ S —CH₂—CH═CH—CH₂— 252 N(iProp) OMe Ph tBut Cl CH₂ CH₂—N—CH₂ S —(CH₂)₅— 253 N(nProp) OMe 2-Napht tBut Me CH₂ CH═C—CH₂ —CH₂— —(CH₂)₃— 254 N(nProp) NCH₂Ph tBut CF₃ OMe CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 255 N(nProp) NHMe tBut H CH₃ CH₂ CH═C—CH₂ S —CH₂—CH(CH₃)—CH₂—

TABLE 10

Example No. Q R2 R6 R7 R8 R9 W X—Y—Z A B 256 NCH₃ NH₂ tBut H tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 257 S OH tBut CN H H CH₂ CH₂—N—CH₂ S —(CH₂)₈— 258 N(iProp) NHMe tBut H Cl H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 259 NCH₃ NH₂ H CN tBu H CH₂ CH₂—CH═C —CH₂— —CH₂CH(CH₃)—CH₂— 260 NCH₃ NHMe CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃— 261 N(cProp) NH₂ nProp H iProp H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—C(═CH₂)—CH₂— 262 S NHMe H H iProp H CH₂ CH₂—CH═C S —(CH₂)₁₀— 263 NCH₃ NH₂ tBut H tBut H CH₂—CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂13 264 N(iProp) NH₂ tBut CN H H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 265 NOH NHMe tBut H H OMe CH₂ CH₂—CH═C O —(CH₂)₃— 266 NCH₃ OH H CN tBu H CH₂ CH═C—CH₂ S —CH₂—CH(CH₃)—CH₂— 267 NEt NH₂ CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 268 S NH₂ nProp H iProp H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 269 NCH₃ NH₂ nProp CN tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₄— 270 NCH₃ OH CF₃ CN iProp H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₃— 271 N(iProp) NHMe Ph C═CH tBut H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 272 S NH₂ tBut CN tBut H CH₂—CH₂ CH₂—CH═C —CH₂— —CH₂—CH(CH₃)—CH₂— 273 NCH₃ NHMe tBut H nProp OMe CH₂ CH₂—N—CH₂ S —(CH₂)₃— 274 N(cProp) NH₂ Ph H tBut H CH₂ CH═C—CH₂ —CH₂— —(CH₂)₄— 275 S NHMe CF₃ H tBut H CH₂—CH₂ CH₂—CH═C S —(CH₂)₃— 276 NCH₃ NH₂ tBut F H Me CH₂ CH₂—N—CH₂ NH —CH₂—CH═CH—CH₂— 277 S NH₂ nProp CN tBut Me CH₂—CH₂ CH═C—CH₂ S —CH₂—C(═CH₂)—CH₂— 278 NCH₃ OH nProp C═CH tBut OMe CH₂ CH═C—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 279 N(iProp) OMe tBut CN H H CH₂ CH₂—N—CH₂ S —(CH₂)₄— 280 NCH₃ OMe H H iProp H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₃—

TABLE 11

Example No. Q R2 R5 R7 R8 R9 W X—Y—Z A B 281 NCH₃ NH₂ H CN tBut H CH₂ CH═C—CH₂— —CH₂— —CH₂—C(═CH₂)—CH₂— 282 NCH₃ NHMe H F tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 283 N(cProp) NH₂ Me Cl iProp H CH₂ CH₂—CH═C —CH₂— —(CH₂)₃— 284 S NHMe H H iProp H CH₂—CH₂ CH═C—CH₂ S —(CH₂)₁₀— 285 NCH₃ NH₂ H H tBut OMe CH₂—CH₂ CH₂—N—CH₂ NH —CH₂—CH(CH₃)—CH₂— 286 N(iProp) NH₂ CN H CF₃ H CH₂ CH₂—N—CH₂ S —(CH₂)₄— 287 S NHMe H CN tBut H CH₂ CH₂—N—CH₂ O —(CH₂)₈— 288 S OH H H tBu H CH₂—CH₂ CH═C—CH₂ S —CH₂—C(═CH₂)—CH₂— 289 NEt NH₂ H CN CHF₂ H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 290 NCH₃ NH₂ Me H iProp H CH₂ CH₂—CH═C S —(CH₂)₃— 291 N(iProp) NH₂ F CN tBut H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₄— 292 S NH₂ OMe Me tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₁₀— 293 NCH₃ NHMe H CN tBut F CH₂—CH₂ CH₂—N—CH₂ NH —CH₂—CH(CH₃)—CH₂— 294 NCH₃ NH₂ H C═CH tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—C(CH₃)═CH—CH₂— 295 N(iProp) NH₂ H Cl CF₃ Me CH₂ CH₂—N—CH₂ S —(CH₂)₅— 296 NEt NHMe H CN tBut Me CH₂—CH₂ CH₂—CH═C —CH₂— —CH₂—C(═CH₂)—CH₂— 297 S OH H C═CH iProp Me CH₂ CH₂—CH═C S —(CH₂)₈— 298 NCH₃ OH Cl H iProp H CH₂ CH₂—N—CH₂ S —(CH₂)₃—

TABLE 12

Example No. Q R2 R5 R6 R8 R9 W X—Y—Z A B 299 NCH₃ NH₂ H tBut tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 300 S OH H tBut Ph H CH₂ CH₂—N—CH₂ S —CH₂—C(═CH₂)—CH₂— 301 N(iProp) NHMe H tBut 1-Pyrrolyl H CH₂ CH₂—N—CH₂ NH —CH₂—CH═CH—CH₂— 302 NCH₃ NH₂ H nPropyl tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 303 NCH₃ NHMe H CF₃ tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃— 304 N(cProp) NH₂ H 2-Napht tBut H CH₂—CH₂ CH═C—CH₂ —CH₂— —(CH₂)₃— 305 S NHMe H tBut H H CH₂—CH₂ CH₂—CH═C S —(CH₂)₈— 306 NCH₃ NH₂ H iProp CHF₂ H CH₂ CH₂—N—CH₂ NH —CH₂—C(═CH₂)—CH₂— 307 N(iProp) NH₂ OMe H CF₃ H CH₂ CH₂—N—CH₂ S —(CH₂)₄— 308 NOH NHMe H tBut H F CH₂—CH₂ CH₂—CH═C O —(CH₂)₃— 309 NCH₃ OH H iProp H Me CH₂ CH═C—CH₂ S —CH₂—C(CH₃)═CH—CH₂— 310 NEt NH₂ CN tBut H H CH₂ CH₂—N—CH₂ —CH₂— —(CH₂)₃— 311 NCH₃ NH₂ H H CF₃ Me CH₂ CH₂—N—CH₂ S —(CH₂)₃— 312 S NHMe H 1-Pyrrolyl H H CH₂—CH₂ CH₂—N—CH₂ S —(CH₂)₁₀— 313 NCH₃ OH H CF₃ tBut H CH₂ CH═C—CH₂ NH —CH₂—C(═CH₂)—CH₂— 314 NEt NH₂ Me tBut nProp H CH₂—CH₂ CH₂—CH═C —CH₂— —CH₂—CH(CH₃)—CH₂— 315 NCH₃ NH₂ Me tBut H H CH₂ CH₂—N—CH₂ S —(CH₂)₅— 316 NH₂ H tBut tBut H CH₂ CH═C—CH₂ —CH₂— —CH₂—CH(CH₃)—CH₂— 317 N(iProp) NH₂ Me CF₃ tBut H CH₂—CH₂ CH₂—CH═C S —(CH₂)₄— 318 NCH₃ OH H nProp tBut H CH₂ CH₂—N—CH₂ S —(CH₂)₃—

TABLE 13

Example No. R1 R2 R3 R6 R7 R8 R9 R10 W X—Y—Z B 319 H Br H H tBut H Me H CH₂ CH₂—N—CH₂ —(CH₂)₄— 320 H I H H tBut H Ph H CH₂—CH₂ CH═C—CH₂ —(CH₂)₄— 321 H Ph H H tBut H 1-Pyrrolyl H CH₂ CH═C—CH₂ —(CH₂)₄— 322 H p(iProp)-Ph H H iProp H 2-Napht H CH₂—CH₂ CH₂—CH═C —(CH₂)₄— 323 H pAcetyl-Ph H H Et H tBut H CH₂ CH₂—N—CH₂ —(CH₂)₃— 324 H pBr-Ph H H Et H tBut H CH₂ CH₂—N—CH₂ —(CH₂)₃— 325 H pI-Ph H OMe CF₃ H H H CH₂ CH═C—CH₂ —(CH₂)₄— 326 H iProp H H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 327 H tBut H H iProp H H H CH₂ CH₂—N—CH₂ —(CH₂)₄— 328 H CN H H H CN tBut H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₃— 329 H COOEt H H H F tBut H CH₂—CH₂ CH₂—CH═C —(CH₂)₄— 330 H OPh H H H Cl iProp H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 331 Me Br H H tBut H H OMe CH₂ CH₂—CH—C —(CH₂)₄— 332 CN I H H iProp H H H CH₂ CH₂—N—CH₂ —(CH₂)₄— 333 Me Ph H H CHF₂ H tBut H CH₂—CH₂ CH═C—CH₂ —(CH₂)₃— 334 F p(iProp)-Ph H OMe tBut H CF₃ H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 335 Me pAcetyl-Ph H H CF₃ H tBut H CH₂ CH₂—N—CH₂ —(CH₂)₅— 336 H pBr-Ph Me H nProp CN tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 337 H pI-Ph F H CF₃ CN iProp H CH₂ CH═C—CH₂ —(CH₂)₄— 338 H iProp Me H Ph C═CH tBut H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 339 H tBut CN H tBut CN H H CH₂ CH₂—CH═C —(CH₂)₄— 340 H CN Me H tBut CN CF₃ OMe CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₅— 341 H COOEt Me H nProp F tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 342 H OPh F H Ph CN tBut Me CH₂ CH₂—CH═C —(CH₂)₃— 343 Cl F H H tBut F H H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 344 H Br H H tBut H Me H CH₂ CH₂—N—CH₂ —CH₂—(═CH₂)_(—CH) ₂— 345 H I H H tBut H Ph H CH₂ CH₂—CH═C —CH₂—C(═CH₂)—CH₂— 346 H Ph H H tBut H 1-Pyrrolyl H CH₂—CH₂ CH═C—CH₂ —CH₂—C(═CH₂)—CH₂— 347 H NEt₂ H H iProp H 2-Napht H CH₂—CH₂ CH₂—CH═C —CH₂—C(CH₃)═CH—CH₂— 348 H pAcetyl-Ph H H Et H tBut H CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 349 H pBr-Ph H H CHF₂ H H H CH₂—CH₂ CH═C—CH₂ —CH₂—C(═CH₂)—CH₂— 350 H pI-Ph H F CF₃ H H H CH₂ CH₂—CH═C —CH₂—CH(CH₃)—CH₂— 351 H iProp H H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 352 H tBut H H iProp H H H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 353 H CN H H H CN tBut H CH₂ CH₂—N—CH₂ —CH₂—CH═CH—CH₂— 354 H COOEt H H H F tBut H CH₂—CH₂ CH₂—CH═C —CH₂—C(CH₃)═CH—CH₂— 355 H OPh H H H Cl iProp H CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 356 Me Br H H tBut H H OMe CH₂ CH₂—CH═C —CH₂—CH(CH₃)—CH₂— 357 Me I H H iProp H H OMe CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 358 Cl Ph H H CHF₂ H tBut H CH₂—CH₂ CH₂CH═C —CH₂—C(═CH₂)—CH₂— 359 CN p(iProp)-Ph H OMe tBut H CF₃ H CH₂ CH₂—N—CH₂ —CH₂—CH═CH—CH₂— 360 F pAcetyl-Ph H OMe CF₃ H tBut H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 361 Me pBr-Ph H H nProp CN tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(CH₃)═CH—CH₂— 362 H pI-Ph CN H CF₃ CN iProp H CH₂ CH₂—CH═C —CH₂—CH(CH₃)—CH₂— 363 H iProp Cl H Ph C═CH tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 364 H tBut F H tBut CN H H CH₂ CH₂—CH═C —CH₂—C(CH₃)═CH—CH₂— 365 H CN Cl H tBut CN CF₃ OMe CH₂—CH₂ CH₂—N—CH₂ —CH₂—CH═CH—CH₂— 366 H COOEt CN H nProp F tBut H CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 367 H OPh Cl H Ph CN tBut Me CH₂—CH₂ CH₂—CH═C —CH₂—C(CH₃)═CH—CH₂— 368 H F Me H tBut F H H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂—

TABLE 14

Example No. R1 R2 R3 R7 R9 R10 W X—Y—Z B 369 H Br H tBut Ph H CH₂ CH₂—N—CH₂ —(CH₂)₄— 370 H I H tBut 2-Napht H CH₂ CH₂—N—CH₂ —(CH₂)₄— 371 H Ph H tBut 1-Pyrrolyl H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 372 H p(iProp)-Ph H tBut cHex H CH₂—CH₂ CH═C—CH₂ —CH₂—C(CH₃)═CH—CH₂— 373 H pAcetyl-Ph H tBut nHex H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 374 H pBr-Ph H tBut H OMe CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 375 H pI-Ph H iProp F H CH₂—CH₂ CH₂—N—CH₂ —CH₂—CH═CH—CH₂— 376 H iProp H CH₃ 1-Pyrrolyl H CH₂ CH₂—C═CH —(CH₂)₄— 377 H tBut H OMe 1-Pyrrolyl H CH₂ CH₂N—CH₂ —CH₂—CH(CH₃)—CH₂— 378 H CN H tBut H CH₃ CH₂—CH₂ CH═C—CH₂ —CH₂—(CH₃)—CH₂— 379 H COOEt H tBut tBut OMe CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 380 H OPh H tBut iProp H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 381 Me Br H Ph tBut Cl CH₂ CH₂—C═CH —CH₂—C(CH₃)═CH—CH₂— 382 CN I H 2-Napht tBut Me CH₂—CH₂ CH═C—CH₂ —(CH₂)₄— 383 Me Ph H tBut CF₃ Me CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂—

TABLE 15

Example No. R1 R2 R3 R7 R8 R9 R10 W X—Y—Z B 384 H Br H tBut H tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 385 H I H tBut CN H H CH₂ CH₂—N—CH₂ —(CH₂)₄— 386 H Ph H tBut H Cl H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 387 H p(iProp)-Ph H H CN tBu H CH₂—CH₂ CH₂—N═C —CH₂—CH(CH₃)—CH₂— 388 H pAcetyl-Ph H CF₃ H tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 389 H pBr-Ph H nProp H iProp H CH₂—CH₂ CH═C—CH₂ —CH₂—CH(CH₃)—CH₂— 390 H pI-Ph H H H iProp OMe CH₂—CH₂ CH₂—CH═C —(CH₂)₄— 391 H iProp H tBut H tBut H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 392 H tBut H tBut CN H H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 393 H CN H tBut H Cl H CH₂ CH₂—N—CH₂ —(CH₂)₃— 394 H COOEt H H CN tBu H CH₂ CH═C—CH₂ —CH₂—C(CH₃)═CH—CH₂— 395 H OPh H CF₃ H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 396 Me Br H nProp H iProp H CH₂ CH₂—N—CH₂ —(CH₂)₄— 397 CN I H H H iProp OMe CH₂ CH₂—N—CH₂ —(CH₂)₄— 398 Me Ph H nProp CN tBut H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 399 F p(iProp)-Ph H CF₃ CN iProp H CH₂—CH₂ CH₂—CH═C —(CH₂)₄ 400 Me pAcetyl-Ph H Ph C═CH tBut H CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 401 H pBr-Ph Me tBut CN tBut H CH₂—CH₂ CH═C—CH₂ —CH₂—CH(CH₃)—CH₂— 402 H pI-Ph F tBut H nProp H CH₂ CH₂—N—CH₂ —(CH₂)₃— 403 H iProp Me Ph H tBut OMe CH₂ CH₂—CH═C —(CH₂)₅— 404 H tBut CN CF₃ H tBut F CH₂—CH₂ CH═C—CH₂ —CH₂—CH(CH₃)—CH₂— 405 H CN Me tBut F H Me CH₂ CH₂—N—CH₂ —CH₂—CH═CH—CH₂— 406 H COOEt Me nProp CN tBut Me CH₂—CH₂ CH₂—CH═C —CH₂—C(═CH₂)—CH₂— 407 H pAcetyl-Ph F nProp C═CH tBut H CH₂ CH═C—CH₂ —CH₂—C(CH₃)═CH—CH₂— 408 Cl F H tBut CN H Me CH₂ CH₂—N—CH₂ —(CH₂)₄—

TABLE 16

Example No. R1 R2 R3 R6 R8 R9 R10 W X—Y—Z B 409 H Br H OMe H tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 410 H I H OMe H CF₃ H CH₂ CH₂—N—CH₂ —(CH₂)₄— 411 H Ph H OMe H tBut H CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 412 H p(iProp)-Ph H H CN tBut H CH₂ CH═C—CH₂ —CH₂—C(CH₃)═CH—CH₂— 413 H pAcetyl-Ph H H F tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 414 H pBr-Ph H Me Cl iProp H CH₂ CH₂—CH═C —CH₂—C(═CH₂)—CH₂— 415 H pI-Ph H H H iProp H CH₂—CH₂ CH═C—CH₂ —(CH₂)₄— 416 H iProp H H H tBut OMe CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 417 H tBut H CN H CF₃ H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 418 H CN H H CN H OMe CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 419 H COOEt H H H tBu F CH₂ CH₂—CH═C —CH₂—C(CH₃)═CH—CH₂— 420 H OPh H H CN tBut H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₃— 421 Me Br H Me H iProp H CH₂ CH₂—N—CH₂ —(CH₂)₄— 422 CN I H OMe H iProp H CH₂—CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 423 Me Ph H OMe CN tBut H CH₂ CH═C—CH₂ —(CH₂)₄—

TABLE 17

Example No. R1 R2 R3 R6 R7 R9 R10 W X—Y—Z B 430 H Br H H tBut tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 431 H I H H tBut Ph H CH₂ CH₂—N—CH₂ —(CH₂)₄— 432 H Ph H H tBut 1-Pyrrolyl H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 433 H p(iProp)-Ph H H nPropyl tBut H CH₂—CH₂ CH₂—N═C —CH₂—C(CH₃)═CH—CH₂— 434 H pAcetyl-Ph H H CF₃ tBut H CH₂ CH₂—N—CH₂ —(CH₂)₄— 435 H pBr-Ph H H 2-Napht tBut H CH₂—CH₂ CH—C—CH₂ —CH₂—C(═CH₂)—CH₂— 436 H pI-Ph H OMe tBut H H CH₂—CH₂ CH₂—CH═C —(CH₂)₄— 437 H iProp H OMe iProp H H CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 438 H tBut H OMe H CF₃ H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 439 H CN H H tBut H H CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 440 H COOEt H H iProp H Me CH₂ CH═C—CH₂ —CH₂—C(CH₃)═CH—CH₂— 441 H OPh H CN tBut H H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₃— 442 Me Br H H H CF₃ Me CH₂ CH₂—N—CH₂ —(CH₂)₄— 443 CN I H H nProp tBut H CH₂ CH₂—N—CH₂ —CH₂—CH(CH₃)—CH₂— 444 Me Ph H OMe tBut iProp H CH₂—CH₂ CH₂—N—CH₂ —(CH₂)₄— 445 F p(iProp)-Ph H OMe CF₃ tBut H CH₂—CH₂ CH═C—CH₂ —(CH₂)₄— 446 Me pAcetyl-Ph H Me tBut nProp H CH₂ CH₂—CH═C —CH₂—CH═CH—CH₂ 447 H pBr-Ph Me Me tBut H H CH₂—CH₂ CH₂—N—CH₂ —CH₂—C(═CH₂)—CH₂— 448 H pI-Ph F H tBut tBut H CH₂ CH═C—CH₂ —(CH₂)₃— 449 H IProp Me Me CF₃ tBut H CH₂ CH₂—CH═C —CH₂—CH(CH₃)—CH₂—

Examples of pharmaceutical presentations

A) Tablets Tablets of the following composition were compressed in a tabletting machine in a conventional way: 40 mg of substance of Example 1 120 mg of corn starch 13.5 mg of gelatin 45 mg of lactose 2.25 mg of Aerosil ® (chemically pure silica in submicroscopically fine distribution) 6.75 mg of potato starch (as 6% paste) B) Coated tablets 20 mg of substance from Example 4 60 mg of core composition 70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone/vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of sucrose, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The coated tablets produced in this way are subsequently provided with an enteric coating.

Biological investigations—receptor-binding studies

1) D₃ binding assay

Cloned CCL 1,3 mouse fibroblasts which express the human D₃ receptor and which are obtainable from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were employed for the binding studies.

Cell preparation

The D₃ expressing cells were grown in RPMI-1640 with 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U/ml penicillin and 0.2% streptomycin (GIBCO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. After neutralization with medium, the cells were collected by centrifugation at 300 g. For cell lysis, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4° C. for 30 min. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.

Binding assays

For the D₃ receptor binding assay, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA) at a concentration of about 106 cells/250 Al of assay mixture and incubated with 0.1 nM ¹²⁵I-sulpiride in the presence and absence of test substance at 30° C. The non-specific binding was determined with 10⁻⁶ M spiperone.

After 60 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) separated the free and the bound radioligand, and the filters were washed with ice-cold tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by non-linear regression analysis using the LIGAND program.

2) D₂ binding assay

Cell culture

HEK-293 cells with stably expressed human dopamine D2A receptors were cultivated in RPMI 1640 with Glutamax I™ and 25 mM HEPES with 10% fetal calf serum albumin. All the media contained 100 units of penicillin per ml and 100 μg/ml streptomycin. The cells ere maintained at 37° C. in a moist atmosphere with 5% CO₂.

The cells were prepared for binding studies by trypsinization (0.05% trypsin solution) at room temperature for 3-5 minutes. The cells were then centrifuged at 250 g for 10 minutes and treated with lysis buffer (5 mM tris-HCl, 10% glycerol, pH 7.4) at 4° C. for 30 minutes. After centrifugation at 250 g for 10 minutes, the residue was stored at −20° C. until used.

Receptor binding assays

1) Dopamine D₂ receptor “low affinity state” with ¹²⁵I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)

The mixtures (1 ml) consisted of 1×10⁵ cells in incubation buffer (50 mM tris,120 mM NaCl, 5 mM KCl, 2 mM MgCl₂ and 2 mM CaCl₂, pH 7.4 with HCl) and 0.1 nM ¹²⁵I-spiperone (total binding) or with the addition of 1 VM haloperidol (nonspecific binding) or test substance.

After incubation at 25° C. for 60 minutes, the mixtures were filtered through GF/B glass fiber filters (Whatman, England) in a skatron cell collector (Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM tris-HCl buffer, pH 7.4. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

Evaluation took place as under a).

The K_(i) values were determined by nonlinear regression analysis using the ligand program or by conversion of the IC₅₀ values using the formula of Cheng and Prusoff.

In these assays, the compounds according to the invention show very good affinities on the D₃ receptor and high selectivities for the D₃ receptor.

The compounds listed below were obtained in a similar way:

Ex. No. Ar¹ A Ar² M. p. [° C.] 450

1 80-90 1 (Oxalate) 451

110-113 452

106-108 453

129-131 454

—S—(CH₂)₃—

1 227-131 1 (Hydrochloride) 455

—S—(CH₂)₃—

1 165-166 1 (Hydrochloride) 456

—(CH₂)₅—

1 115-118 1 (Oxalate) 457

—(CH₂)₄—

1 94-97 1 (Hydrochloride) 458

—(CH₂)₄—

1 123-126 1 (Fumarate) 459

1 130-133 1 (Fumarate) 460

1 118-125 1 (Fumarate) 461

1 130-132 1 (Oxalate) 462

—(CH₂)₆—

1 144-150 1 (Fumarate) 463

—(CH₂)₄—

1 148-154 1 (Oxalate) 464

1 171-176 1 (Fumarate) 465

—(CH₂)₄—

1 122-124 1 (Fumarate) 466

—(CH₂)₄—

1 108-112 1 (Oxalate) 467

—(CH₂)₄—

1 140-142 1 (Oxalate) 468

—(CH₂)₄—

1 149-152 1 (Fumarate) 469

—(CH₂)₄—

1 147-149 1 (Hydrochloride) 470

—(CH₂)₄—

1 235-236 1 (Fumarate) 471

92-98 472

87-90 473

—(CH₂)₄—

1 112-115 1 (Fumarate) 474

—(CH₂)₆—

1 101-105 1 (Oxalate) 475

—(CH₂)₄—

1 127-129 1 (Oxalate) 476

—S—(CH₂)₃—

477

—S—(CH₂)₃—

478

—S—(CH₂)₃—

1 126-128 1 (Fumarate) 479

—S—(CH₂)₃—

1 150-156 1 (Fumarate) 480

—S—(CH₂)₃—

1 158-165 1 (Fumarate) 481

—S—(CH₂)₃—

482

—S—(CH₂)₃—

1 184-188 1 (Oxalate) 483

—S—(CH₂)₃—

1 185-187 1 (Oxalate) 484

485

127 486

128 487

—S—(CH₂)₃—

123 488

—S—(CH₂)₃—

120 489

—S—(CH₂)₃—

1 187-191 1 (Oxalate) 490

—S—(CH₂)₃—

1 187-191 1 (Oxalate) 491

—S—(CH₂)₃—

492

—S—(CH₂)₃—

493

—S—(CH₂)₃—

494

—S—(CH₂)₃—

1 93-94 1 (Oxalate) 495

—S—(CH₂)₃—

496

—S—(CH₂)₃—

1 168-170 1 (Fumarate) 497

—S—(CH₂)₃—

498

—S—(CH₂)₃—

499

500

—S—(CH₂)₃—

501

—S—(CH₂)₃—

502

503

504

505

—S—(CH₂)₃—

506

—S—(CH₂)₃—

507

508

509

510

511

—S—(CH₂)₃—

512

—S—(CH₂)₃—

513

514

515

—S—(CH₂)₃—

516

—S—(CH₂)₃—

81-85 517

518

519

520

75-80 521

1 110-112 1 (Hydrochloride) 522

—S—(CH₂)₃—

78-80 523

1 95-97 1 (Hydrochloride) 524

142-145 525

80-91 526

Oxalate 527

—S—(CH₂)₈—

Hydrochloride 528

—S—(CH₂)₃—

Oxalate 529

—S—(CH₂)₃—

DiHydrochloride 530

Oxalate 531

532

533

534

95-96 535

—S—(CH₂)₃—

 92 536

—S—(CH₂)₃—

 90 537

 97 538

—S—(CH₂)₃—

 98-100 539

540

541

—S—(CH₂)₃—

66-72 542

—S—(CH₂)₃—

543

—S—(CH₂)₃—

544

—S—(CH₂)₃—

545

—S—(CH₂)₃—

546

—S—(CH₂)₃—

547

—S—(CH₂)₃—

548

—S—(CH₂)₃—

549

—S—(CH₂)₃—

550

—S—(CH₂)₃—

551

—S—(CH₂)₃—

552

553

554

555

556

557

558

100-103 559

—S—(CH₂)₃—

560

—S—(CH₂)₃—

109-112 561

—S—(CH₂)₃—

562

—S—(CH₂)₃—

563

—S—(CH₂)₃—

564

—S—(CH₂)₃—

565

84-85 566

567

568

—S—(CH₂)₃—

569

—S—(CH₂)₃—

570

—S—(CH₂)₃—

571

—S—(CH₂)₃—

572

—S—(CH₂)₃—

573

—S—(CH₂)₃—

185-190 574

145-148 575

120-122 576

1 70-80 1 (Oxalate) 577

1 155-160 1 (Hydrochloride) 578

—S—(CH₂)₃—

1 97-98 1 (Hydrochloride) 579

1 141-143 1 (Fumarate) 580

1 105-108 1 (Hydrochloride) 581

1 139-143 1 (Hydrochloride) 582

89-95 583

—S—(CH₂)₃—

1 160-165 1 (Oxalate) 584

—(CH₂)₄—

62-64 585

—(CH₂)₄—

148-149 586

—(CH₂)₄—

38-41 587

—CH═CH—(CH₂)₂—

Oil 588

—S—(CH₂)₃—

1 90 1 (Decomposition) 1 (Hydrochloride) 589

—S—(CH₂)₃—

1 90-93 1 (Fumarate) 590

—S—(CH₂)₃—

1 75-78 1 (Fumarate) 591

Oil 592

—S—(CH₂)₃—

1 130-133 1 (Hyrochlorid) 593

—S—(CH₂)₃—

Oil 594

1 126-130 1 (Hydrochloride) 595

—S—(CH₂)₃—

1 90-95 1 (Decomposition) 1 (Hydrochloride) 596

Oil 597

—S—(CH₂)₃—

Oil 598

—S—(CH₂)₃—

1 106 1 (Hydrochloride) 599

—S—(CH₂)₃—

1 148 1 (Hydrochloride) 600

—S—(CH₂)₃—

1 137-139 1 (Hydrochloride) 601

1 109-115 1 (Hydrochloride) 602

—S—(CH₂)₃—

1 90 1 (Decomposition) 1 (Hydrochloride) 603

1 132 1 (Decomposition) 1 (Hydrochloride) 604

1 103-105 1 (Hydrochloride) 605

—S—(CH₂)₃—

142-144 606

—S—(CH₂)₃—

Oil 607

—S—(CH₂)₃—

Oil 608

—S—(CH₂)₃—

1 120-123 1 (Hydrochloride) 609

—S—(CH₂)₃—

1 187-189 1 (Fumarate) 610

1 95-98 1 (Fumarate) 611

1 68-72 1 (Fumarate) 612

—S—(CH₂)₃—

1 240 1 (Hydrochloride) 613

1 190 1 (Hydrochloride) 614

—S—(CH₂)₃—

1 243 1 (Hydrochloride) 615

—S—(CH₂)₃—

101-104 616

—S—(CH₂)₃—

Oil 617

1 90-94 1 (Decomposition) 1 (Hydrochloride) 618

1 152 1 (Hydrochloride) 619

—S—(CH₂)₃—

Oil 620

—S—(CH₂)₃—

Oil 621

1 152 1 (Hydrochloride) 622

—S—(CH₂)₃—

1 110 1 (Hydrochloride) 623

—S—(CH₂)₃—

1 126-131 1 (Hydrochloride) 624

—S—(CH₂)₃—

1 91 1 (Hydrochloride) 625

—S—(CH₂)₃—

1 116-120 1 (Hydrochloride) 626

1 103 1 (Hydrochloride) 627

—S—(CH₂)₃—

1 150 1 (Hydrochloride) 628

1 140 1 (Hydrochloride) 629

—S—(CH₂)₃—

1 130 1 (Hydrochloride) 630

—S—(CH₂)₃—

1 98-104 1 (Hydrochloride) 631

1 65-68 1 (Hydrochloride) 632

—S—(CH₂)₃—

1 131-136 1 (Hydrochloride) 633

1 105 1 (Hydrochloride) 634

1 132 1 (Hydrochloride) 635

1 94 1 (Hydrochloride) 636

1 95 1 (Hydrochloride) 637

1 102 1 (Hydrochloride) 638

—S—(CH₂)₃—

1 214-216 1 (Hydrochloride) 639

—S—(CH₂)₃—

1 160-162 1 (Hydrochloride) 640

—S—(CH₂)₃—

1 73-75 1 (Fumarate) 641

178 642

—S—(CH₂)₃—

155 643

—S—(CH₂)₃—

1 125-128 1 (Hydrochloride) 644

—S—(CH₂)₃—

1 102 1 (Hydrochloride) 645

—S—(CH₂)₃—

1 88 1 (Hydrochloride) 646

—S—(CH₂)₃—

1 132 1 (Hydrochloride) 647

1 190 1 (Hydrochloride) 648

—S—(CH₂)₃—

1 134-138 1 (Hydrochloride) 649

—S—(CH₂)₃—

1 170-174 1 (Hydrochloride) 650

—S—(CH₂)₃—

1 115 1 (Hydrochloride) 651

—S—(CH₂)₃—

1 117 1 (Hydrochloride) 652

151-155 653

1 158-161 1 (Hydrochloride) 654

—S—(CH₂)₃—

1 184-185 1 (Hydrochloride) 655

1 194-195 1 (Hydrochloride) 656

1 114 1 (Hydrochloride) Ph = Phenyl

The compounds listed above which are not characterized by a melting point, have the following NMR spectra (d₆-DMSO):

Ex. no.

476 1,8-2,1 (m,4H); 2,6-2,7 (m,4H); 2,8 (t,2H); 3,2 (t,2H); 3,5-3,7 (b,2H); 3,7-3,9 (b,2H); 4,5 (d,2H); 5,1 (t,1H); 5,2 (s,1H); 6,1 (d,1H); 6,2 (m,2H); 7,3 (m,5H); 7,7 (m,2H); 7,8 (d,1H)

477 1,8-1,9 (m,4H); 2,5-2,6 (m,4H); 2,7 (t,2H); 3,0 (t,2H); 3,3 (s,3H); 3,5-3,8 (b,4H); 4,2 (s,2H); 4,5 (d,2H); 5,1 (t,1H); 5,2 (s,1H); 6,2 (m,2H); 7,3-7,4 (m,5H); 7,7 (m,2H)

481 Oxalate 2,1 (b,4H); 3,2-3,4 (m,8H); 3,6 (s,3H); 3,7 (b,2H); 6,6-6,8 (m,3H); 7,2 (t,1H); 7,6 (m,3H) 7,7 (m,2H)

484 Oxalate 2,0 (b,2H); 2,8-3,0 (b,4H); 3,4-3,5 (m,4H); 3,6-3,7 (b,2H); 3,9 (s,2H); 5,3 (d,2H); 6,1 (d,1H);

6,5-6,8 (m,3H); 7,21 (t,1H); 7,9 (d,1H);

491 Oxalate 2,0-2,3 (b,4H); 3,0-3,4 (b,8H); 3,6 (s,3H); 3,9 (b,2H); 4,1 (b,2H); 7,1-7,3 (b,1H); 7,5 (m,3H); 7,6 (m,2H); 8,6 (s,1H);

492 1,7-1,9 (m,4H); 2,6 (b,2H); 2,8 (b,2H); 3,1 (t,2H); 3,6-3,9 (b,4H); 6,1 (d,1H); 7,0 (d,1H); 7,8 (d,1H); 8,5 (s,1H);

493 Oxalate 1,9-2,1 (b,4H); 2,7 (s,3H); 2,8 (t,2H); 3,0-3,3 (b,6H); 3,3 (s,3H); 3,4 (t,2H); 3,7 (b,2H); 6,3 (b,1H); 6,4-6,5 (m,3H); 7,0 (m,1H);

495 Fumarate 1,6-1,8 (b,4H); 2,6 (m,2H); 2,7 (t,2H); 3,2 (s,3H); 3,3-3,5 (m,4H); 5,9 (s,2H); 6,2-6,5 (m,3H); 7,0 (M,1H);

497 Fumarate 1,6-1,8 (m,2H); 1,8-2,0 (b,2H); 2,5-2,7 (b,4H); 2,8-2,9 (m,4H); 3,2 (s,3H); 3,7-3,9 (m,4H); 5,9 (b,2H); 6,5 (s,2H); 7,4 (d,1H);

498 Fumarate 1,3 (s,9H); 1,8-2,1 (b,4H); 2,7-3,0 (b,6H); 3,3 (s,3H); 3,5-3,8 (b,6H); 6,1 (b,2H); 6,6 (s,2H); 6,7 (s,1H)i

499 Hydrochloride 1,3 (s,9H); 1,9 (b2H); 2,2 (s,2H); 2,5 (b,2H); 2,7 (b,2H); 3,1 (s,2H); 3,4 (s,3H); 3,7 (s,2H); 3,8 (s,3H); 3,9 (s,3H); 5,0 (d,2H); 6,5 (s,1H); 6,9 (d,1H); 7,5 (d,1H); 7,7 (s,1H);11,3 (b,1H);

500 Fumarate 1,3 (s,9H); 1,7-1,9 (b,4H); 2,5-2,7 (b,4H); 2,8-2,9 (b,2H); 3,1 (t,2H); 3,6-3,7 (b,2H); 3,8-4,0 (b,2H); 6,1 (d,1H); 6,6 (s,2H); 6,9 (d,1H); 7,8 (d,1H)

501 1,3 (s,9H); 1,8-2,0 (m,4H); 2,6 (m,4H); 2,8 (b,2H); 3,1 (t,2H); 3,4 (s,3H); 3,5 (b,2H); 3,9-4,1 (b,2H); 4,4 (b,2H); 6,5 (s,1H)

502 Fumarate 1,3 (s,9H); 1,8-1,9 (b,2H); 2,5-2,6 (b,2H); 2,7 (b,2H); 3,1 (s,2H); 3,6-3,7 (b,2H); 3,7-4,0 (m,4H); 5,1 (s,1H); 5,2 (s,1H); 6,1 (d,1H); 6,6 (s,2H); 6,9 (d,1H); 7,8 (d,1H)

503 Fumarate 1,3 (s,9H); 1,8-1,9 (b,2H); 2,5-2,6 (b,2H); 2,7-2,8 (b,2H); 3,2 (s,2H); 3,6 (s,3H); 3,6-3,7 (b,2H); 3,7 (s,2H); 3,8-4,0 (b,2H); 5,0 (s,1H); 5,1 (s,1H); 6,6 (s,2H); 6,9 (d,1H); 7,6 (m,3H); 7,7 (m,2H)

504 Fumarate 1,3 (s,9H); 1,8-1,9 (b,2H); 2,5 (b,2H); 2,6-2,7 (b,2H); 3,1 (s,2H); 3,3 (s,3H); 3,4 (s,2H); 3,5-3,7 (b,2H); 3,8-4,0 (b,2H); 4,9 (d,2H); 6,0 (s,2H); 6,6 (s,2H); 6,9 (d,1H)

505 Fumarate 1,3 (s,9H); 1,7-1,9 (b,4H); 2,5-2,7 (b,4H); 2,8 (t,2H); 3,1 (t,2H); 3,4-4,0 (b,4H); 6,1 (d,1H); 6,5 (d,1H); 6,6 (s,2H); 7,8 (d,1H); 8,2 (d,1H)

506 1,4 (s,9H); 1,8 (m,2H); 2,1-2,2 (b,2H); 2,6 (m,4H); 2,7 (t,2H); 3,0 (t,2H); 3,4 (s,3H); 3,5-4,0 (b,4H); 4,6 (b,2H); 6,2 (d,1H); 8,2 (d,1H)

507 0,9 (t,3H); 1,3 (s,9H); 1,4 (m,2H); 1,7 (m,2H); 2,1 (b,2H); 2,6 (t,2H); 2,7 (t,2H); 2,8 (t,2H); 3,3 (s,2H); 3,6-3,7 (b,2H); 3,8 (s,2H); 3,9-4,0 (b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,1 (s,1H); 6,2 (d,1H); 7,8 (d,1H)

508 0,9 (t,3H); 1,3 (s,9H); 1,4 (m,2H); 1,7 (m,2H); 1,9 (m,2H); 2,6 (m,4H); 2,7 (t,2H); 3,1 (d,3H); 3,2 (s,2H); 3,3 (s,3H); 3,6 (m,1H); 3,7 (s,2H); 3,6-3,8 (b,4H); 5,0 (d,2H); 6,0 (s,1H)

509 Dihydrochloride 0,9 (t,3H); 1,3 (m,2H); 1,4 (s,9H); 1,7 (m,2H); 2,4-2,5 (b,2H); 2,9 (t,2H); 3,2-3,4 (b,4H); 3,5 (s,3H); 3,7-3,8 (b,2H); 3,9 (s,2H); 3,9-4,2 (b,2H); 4,1 (s,2H); 5,4 (s,2H); 6,9 (s,1H);8,5 (s,2H); 11,7 (b,1H); 14,0 (b,1H)

510 1,3 (s,9H); 2,0-2,1 (b,2H); 2,7 (t,2H); 2,8 (t,2H); 3,3 (s,2H); 3,5-3,8 (b,2H); 3,8 (s,2H) 3,8-4,1 (b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,2 (m,2H); 7,8 (d,1H); 8,2 (d,1H)

511 1,3 (s,18H); 1,6-1,9 (b,4H); 2,4 (b,2H); 2,7 (b,2H); 2,8 (t,2H); 3,2 (s,3H); 3,7 (m,4H); 5,8 (s,1H);

512 1,3 (s,18H); 1,7-1,8 (m,4H); 2,5 (b,2H); 2,7 (b,2H); 3,0 (t,2H); 3,7-3,8 (m,4H); 6,0 (d,1H); 7,8 (d,1H);

513 1,6-2,1 (m,17H); 2,7 (s,2H); 3,1 (s,2H); 3,3-3,6 (b,6H); 3,4 (s,3H); 3,8-3,9 (b,2H); 4,8 (b,2H); 6,0 (b,2H); 6,8 (s,1H);

514 1,6-2,0 (m,17H); 2,5 (s,2H); 2,6 (s,2H); 3,0 (s,2H); 3,5-3,9 (b,6H); 5,0 (d,2H); 6,0 (d,1H) 6,8 (d,1H); 7,8 (d,1H);

515 1,7-2,0 (m,19H); 2,5 (b,2H); 2,7 (s,2H); 3,0 (t,2H); 3,5-3,8 (b,4H); 6,0 (d,1H); 6,8 (d,1LH); 7,8 (d,1H);

517 Dihydrochloride 1,4 (s,9H); 2,4-2,5 (b,2H); 3,3-3,6 (b,4H); 3,5 (s,3H); 3,7-3,8 (b,2H); 3,8-3,9 (b,2H); 3,9-4,2 (b,4H); 5,4 (s,2H); 7,1 (d,1H); 8,3 (d,1H); 8,5 (s,2H); 11,7 (b,1H); 14,5 (b,1H)

518 1,3 (s,9H); 1,8-2,0 (b,2H); 2,6 (t,2H); 2,7 (t,2H); 3,0 (d,3H); 3,2 (s,2H); 3,3 (s,3H); 3,6 (s,2H); 3,6-3,9 (b,5H); 5,0 (d,2H); 6,2 (s,1H); 6,3 (m,2H); 7,8 (m,2H)

519 1,4 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H); 3,0 (d,3H); 3,2 (s,2H); 3,3 (s,3H); 3,7 (s,2H); 3,6-3,9 (b,5H); 5,0 (d,2H); 6,1 (s,1H); 6,3 (m,2H); 7,6 (m,2H)

527 Hydrochloride 1,2-1,5 (b,1OH); 1,5-1,8 (b,4H); 3,1 (m,4H); 3,5 (m,4H); 3,8-4,0 (b,4H); 6,8 (t,1H); 6,9 (b,3H); 7,1 (t,1H); 10,5 (b,1H)

526 Oxalate 1,3 (s,9H); 1,9-2,1 (b,2H); 2,7-3,0 (b,4H); 3,4 (b,2H); 3,6 (s,3H); 3,6-3,8 (b,2H); 3,8 (s,2H); 3,9-4,1 (b,2H); 5,2 (d,2H); 6,2 (m,2H); 6,4 (s,1H); 7,6 (m,3H); 7,7 (m,4H)

528 Oxalate 0,9 (t,3H); 1,3 (s,9H); 1,4 (m,2H); 1,6 (m,2H); 1,9-2,2 (b,4H); 2,5 (m,2H); 3,0-3,2 (b,4H); 3,2-3,4 (b,4H); 3,5-3,7 (b,2H); 3,9-4,1 (b,2H); 6,1 (d,1H); 6,4 (s,1H); 7,8 (d,1H)

529 Dihydrochloride 0,9 (t,3H); 1,3 (m,2H); 1,4 (s,9H); 1,7 (m,2H); 2,2 (b,3H); 3,0 (t,2H); 3,2 (b,5H); 3,5 (s,3H); 3,5-4,2 (b,7H); 4,5-4,7 (b,1H); 7,0 (d,1H); 8,6 (s,2H); 11,7 (b,1H); 14,2 (b,1H)

530 Oxalate 1,3 (s,9H); 1,9-2,1 (b,2H); 2,7-3,0 (b,4H); 2,3-2,4 (b,2H); 2,6-4,1 (b,4H); 3,9 (s,2H); 5,2 (s,1H); 5,3 (s,1H); 6,1 (d,1H); 6,2 (m,2H); 6,4 (s,1H); 7,7 (m,2H); 7,8 (d,1H)

531 1,3 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H); 3,2 (s,2H); 3,3 (s,3H); 3,7 (s,2H); 3,6-3,9 (b,4H); 4,3 (s,2H); 5,0 (d,2H); 6,2 (s,1H); 6,3 (m,2H); 7,8 (m,2H)

533 1,3 (s,9H); 2,1 (m,2H); 2,7 (m,2H); 2,9 (m,2H); 3,3 (s,2H); 3,6-3,8 (b,2H); 3,8 (s,2H); 3,9-4,1 (b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,1 (s,1H); 6,2 (d,1H); 6,3 (m,2H); 7,5 (m,2H); 7,8 (d,1H)

532 1,3 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H); 3,2 (s,2H); 3,3 (s,3H); 3,7 (s,2H); 3,6-3,6 (b,4H); 4,3 (s,2H); 5,0 (s,2H); 6,1 (s,1H); 6,3 (m,2H); 7,6 (m,2H)

539 Hydrochloride 2,2-2,3 (b,2H); 3,0-3,2 (b,2H); 3,5-4,0 (b,8H), 4,2 (s,2H); 5,5 (d,2H); 6,2 (d,1H); 6,9-7,0 (m,3H); 7,0 (t,1H); 7,4 (m,1H); 7,9 (d,1H); 10,9 (b,1H);

540 Hydrochloride 2,4 (b,2H); 3,2 (b,4H); 3,4 (s,3H); 3,5 (.m,2H); 3,7 (b,4H); 4,0 (s,2H); 5,3 (d,2H); 6,8-7,1 (m,4H); 7,2-7,4 (m,3H);

542 1,3 (s,9H); 1,9 (m,2H); 1,9-2,1 (b,2H); 2,6 (m,4H); 2,8 (b,2H); 3,2 (t,2H); 3,5-3,7 (b,2H); 3,9-4,2 (b,2H); 6,2 (d,1H); 6,5 (s,1H); 6,8 (d,1H)

543 1,3 (s,9H); 1,9 (m,2H); 1,9-2,0 (b,2H); 2,6-2,7 (b,4H); 2,8 (b,2H); 3,1 (t,2H); 3,2 (s,3H); 3,5-3,6 (b,2H); 3,9-4,1 (b,2H); 6,5 (s,1H); 10,8 (b,1H)

544 1,3 (s,9H); 1,8-2,0 (b,4H); 2,6 (m,4H); 2,7-2,8 (b,2H); 3,0 (m,5H); 3,3 (s,3H); 3,5-3,6 (b,2H) 3,9-4,1 (b,3H); 6,5 (s,1H)

545 Hydrochloride 1,3 (s,9H); 2,1-2,2 (b,3H); 2,5-2,6 (b,1H); 3,1-3,3 (b,6H); 3,4 (s,3H); 3,4-3,8 (b,4H); 4,0-4,1 (b,1H); 4,6-4,7 (b,1H); 7,0 (s,1H); 8,6 (s,2H); 11,3 (b,1H)

546 1,3 (s,9H); 1,9 (m,2H); 2,1 (m,2H); 2,7 (m,4H); 2,9 (m,2H); 3,2 (t,2H); 3,8-3,9 (b,2H); 3,9-4,0 (b,2H); 6,2 (d,2H); 6,3 (m,2H); 7,8 (m,3H)

547 1,3 (s,9H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (t,2H); 3,1 (t,2H); 3,2 (s,3H); 3,6-4,0 (b,4H); 6,2 (s,1H); 6,3 (m,2H); 7,8 (m,2H); 9,2 (s,1H)

548 1,3 (s,9H); 1,9 (m,4H); 2,6 (t,4H); 2,8 (t,2H); 3,1 (t,2H); 3,3 (s,3H); 3,5-3,9 (b,4H); 4,1 (s,2H); 6,2 (s,1H); 6,3 (m,2H); 7,8 (m,2H)

549 1,4 (s,9H); 1,9 (m,2H); 2,0-2,1 (b,2H); 2,7 (m,4H); 2,9 (m,2H); 3,2 (t,2H); 3,6-3,8 (b,2H); 3,8-4,1 (b,2H); 6,1 (s,1H); 6,2 (d,1H); 6,3 (m,2H); 7,6 (m,2H), 7,8 (d,1H)

550 1,4 (s,9H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (b,2H); 3,1 (t,2H); 3,2 (s,3H); 3,6-4,0 (b,4H); 6,1 (s,1H); 6,3 (m,2H); 7,5 (m,2H); 10,0 (b,1H)

551 1,4 (s,9H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (b,2H); 3,1 (t,2H); 3,4 (s,3H); 3,5-4,0 (b,4H); 4,3 (s,2H); 6,1 (s,1H); 6,3 (m,2H); 7,5 (m,2H)

552 1,3 (s,9H); 2,1 (m,2H); 2,8 (m,2H); 2,9 (m,2H); 3,3 (s,2H); 3,8 (s,2H); 3,9 (t,2H); 4,1 (b,2H); 5,1 (s,1H); 5,2 (s,1H); 6,2 (d,1H); 6,5 (d,1H); 7,8 (d,1H); 8,2 (d,1H)

553 Hydrochloride 1,3 (s,9H); 2,2-2,3 (b,1H); 2,5-2,7 (b,1H); 3,1 (s,3H); 3,0-3,2 (b,2H); 3,5-3,7 (b,3H); 3,8-4,1 (m,6H); 4,4-4,5 (b,1H); 5,4 (d,2H); 6,8 (d,1H); 8,3 (d,1H); 11,2 (b,1H); 11,9 (s,1H)

554 1,3 (s,9H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H); 3,2 (s,2H); 3,4 (s,3H); 3,7 (s,2H); 3,8 (m,4H); 4,4 (s,2H); 5,0 (s,2H); 6,5 (d,1H); 8,2 (d,1H)

555 1,3 (s,18H); 2,1 (m,2H); 2,8 (t,2H); 3,0 (t,2H); 3,3 (s,2H); 3,8 (s,2H); 3,9 (t,2H); 4,1 (t,2H); 5,1 (s,1H); 5,2 (s,1H); 6,2 (d,1H); 6,5 (s,1H); 7,8 (d,1H)

556 1,3 (s,18H); 1,9 (m,2H); 2,6 (t,2H); 2,7 (t,2H) 3,2 (s,2H); 3,4 (s,3H); 3,6 (s,2H); 3,9 (m,4H); 4,2 (s,2H); 5,0 (s,2H); 6,5 (s,1H)

557 Hydrochloride 1,3 (d,6H); 2,2 (b,1H); 2,6 (b,1H); 3,0 (b,4H)i 3,4 (s,3H); 3,5-3,7 (b,4H); 3,8 (s,2H); 4,1 (s,2H); 5,4 (s,2H); 6,8 (t,1H); 6,9 (s,1H); 8,5 (b,2H); 11,6 (b,1H);

559 Hydrochloride 1,2 (d,6H); 2,1 (b,4H); 3,0-3,2 (b,8H); 3,5-4,2 (b,4H); 6,1 (d,1H); 6,8 (t,1H); 6,9 (b,1H); 7,8 (d,1H); 11,3 (b,1H)

561 1,3 (s,18H); 1,9 (m,2H); 2,0 (m,2H); 2,7 (t,2H); 2,8 (t,2H); 3,0 (t,2H); 3,2 (t,2H); 3,9 (t,2H); 4,0 (t,2H); 6,1 (d,1H); 6,5 (s,1H); 7,8 (d,1H)

562 1,3 (s,18H); 1,9 (m,4H); 2,6 (m,4H); 2,8 (t,2H); 3,0 (t,2H); 3,4 (s,3H); 3,8 (t,2H); 3,9 (t,2H); 4,3 (s,2H); 6,5 (s,1H)

564 Oxalate 1,3 (s,9H); 2,0 (b,2H); 2,2 (b,2H); 3,1-3,4 (b,8H); 3,3 (b,2H); 3,8 (s,3H); 4,0 (b,2H); 6,1 (d,2H); 6,9 (s,1H); 7,0 (d,1H); 7,8 (d,1H); 8,1 (d,1H);

563 Oxalate 1,3 (s,9H); 1,9 (b,2H); 2,2 (b,2H); 2,9 (t,2H); 3,1 (t,2H); 3,3 (b,4H); 3,4 (s,3H); 3,7 (b,2H); 3,8 (s,3H); 4,0 (b,2H); 5,3 (b,2H); 6,8 (s,1H); 6,9 (d,1H); 8,0 (d,1H);

566 1,4 (s,9H); 1,9 (b,2H); 2,5 (b,2H); 2,8 (b,2H); 3,2 (s,2H); 3,3 (s,3H); 3,6 (s,2H); 3,6-3,8 (b,4H); 3,8 (s,3H); 4,8 (b,2H); 5,0 (s,2H); 6,5 (s,1H); 7,0 (d,1H); 8,0 (d,1H);

567 Oxalate 2,0 (b,2H); 2,8 (b,2H); 3,0 (b,2H); 3,3 (s,3H); 3,4 (s,2H); 3,6 (b,4H); 3,8 (b,2H); 5,1 (s,2H); 5,5 (b,2H); 7,0 (m,2H); 7,7 (t,1H);

568 Oxalate 2,0 (b,2H); 2,2 (b,2H); 3,0 (t,2H); 3,1 (m,2H); 3,2 (b,4H); 3,4 (s,3H); 3,6 (m,2H); 3,9 (b,2H); 6,7 (b,2H); 7,0 (t,2H); 7,7 (t,1H);

569 Oxalate 2,0-2,2 (b,4H); 3,0-3,4 (m,8H); 3,5 (m,2H); 3,9 (b,2H); 6,1 (d,1H); 6,5 (b,2H); 7,0 (t,2H); 7,7 (t,1H); 7,8 (d,1H);

570 Hydrochloride 1,3 (s,9H); 2,0-2,2 (b,3H); 2,3-2,4 (b,1H); 3,2 (m,6H); 3,4-4,0 (b,5H); 4,3-4,5 (b,1H); 6,2 (d,1H); 6,8 (d,1H); 7,9 (d,1H); 8,3 (d,1H); 10,8 (b,1H)

571 Hydrochloride 1,3 (s,9H); 2,0-2,2 (b,3H); 2,3-2,4 (b,1H); 3,1 (s,3H); 3,0-3,2 (m,6H); 3,4-4,0 (b,5H); 4,3-4,5 (b,1H); 6,8 (d,1H); 8,3 (d,1H); 10,9 (b,1H); 11,9 (s,1H)

572 1,3 (s,9H); 1,9-2,0 (m,4H); 2,6 (m,4H); 2,8 (t,2H); 3,0 (t,2H); 3,4 (s,3H); 3,8 (t,2H); 3,9 (b,2H); 4,6 (b,2H); 6,5 (d,1H); 8,2 (d,1H) 

We claim:
 1. A compound of the formula I Ar¹—A—B—Ar²  (I) where Ar¹ is a 6-membered heteroaromatic ring with 1 or 2 heteronitrogen atoms, where Ar¹ may have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR¹, alkyl which is unsubstituted or substituted by OH, OC₁-C₈-alkyl or halogen, or C₂-C₆-alkenyl, C₂-C₆-alkynyl, cycloalkyl, halogen, CN, CO₂R¹, NO₂, NR¹R², SR¹, CF₃, CHF₂, phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl, acyl, phenyl, amino, nitro, cyano or halogen, or phenoxy which is unsubstituted or substituted by C₁-C₆-alkyl, OC₁-C₆-alkyl or halogen, or C₁-C₆-alkanoyl or benzoyl; R¹ is H, alkyl which is unsubstituted or substituted by OH, OC₁-C₆-alkyl, phenyl or halogen; R² has the meanings stated for R¹ or is COR¹ or CO₂R¹; A is a C₄-C₁₅-alkylene group or a C₃-C₁₅-alkylene group which comprises at least one group Z which is selected from O, S, NR¹, a double and a triple bond, where R¹ is as defined above, B is a 7- or 8-membered saturated ring with two nitrogen heteroatoms, the nitrogen heteroatoms being located in the 1,4 or 1,5 position and the ring being bonded in position 1 to the radical A and in position 4 or 5 to the radical Ar², and it additionally being possible for the ring to have a double bond in position 3 or 4; Ar² is phenyl, pyridyl, or pyrimidinyl, it being possible for Ar² to have 1, 2, 3 or 4 substituents which are selected, independently of one another, from OR¹, alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, alkoxyalkyl, haloalkyl, halogen, CN, CO₂ R¹, NO₂, SO₂ R¹, NR¹ R², SO₂N R¹ R², SR¹, a 5- or 6-membered carbocyclic, aromatic or non-aromatic ring and a 5- or 6-membered heterocyclic aromatic or non-aromatic ring with 1 to 3 heteroatoms which are selected from O, S and N. the carbocyclic or heterocyclic ring being unsubstituted or substituted by C₁-C₈-alkyl, phenyl, halogen, OC₁-C₈-alkyl, OH, NO₂ or CF₃, and Ar² may also be fused to a carbocyclic ring of the type defined above, and where Ar² cannot be a pyrimidinyl radical substituted by 2 hydroxyl groups, and the salts thereof with physiologically tolerated acids.
 2. A compound as claimed in claim 1 of the formula I where Ar¹ is

where R³to R⁵ are, independently of one another, H or the substituents mentioned in claim 1 for the radical Ar¹.
 3. A compound as claimed in claim 1 of the formula I where Ar¹ is

where R³ to R⁵ have the meanings stated in claim
 2. 4. A compound as claimed in claim 3 of the formula I where R³, R⁴ and R⁵ are, independently of one another, H, OR¹, alkyl, NR¹R², halogen, phenoxy, CN, phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, acyl or halogen, or COOR¹; R¹ and R² are, independently of one another, H, alkyl or benzyl.
 5. A compound as claimed in claim 4, where R³ to R⁶ are selected, independently of one another, from H, C₁-C₆-alkyl, OR¹, NR¹R², phenyl which is unsubstituted or substituted by C₁-C₆-alkyl, acyl or halogen, and halogen, where R¹ and R² have the abovementioned meanings.
 6. A compound as claimed in claim 5, where Ar¹ is pyrimidinyl which is unsubstituted or substituted by OH, Oalkyl or Obenzyl.
 7. A compound as claimed in any of the preceding claims of the formula I, where A is —Z—C₃-C₆-alkylene, in particular —Z—CH₂CH₂CH₂—, —Z—CH₂CH₂CH₂CH₂—, —Z—CH₂CH═CHCH₂—, —Z—CH₂C(CH₃)═CHCH₂—, —Z—CH₂C(═CH₂)CH₂—, —Z—CH₂CH(CH₃)CH₂— or a linear —Z—C₇-C₁₀-alkylene radical, where Z is bonded to Ar¹ and is CH₂, O or S.
 8. A compound as claimed in claim 1 of the formula I, where B is


9. A compound as claimed in claim 1 of the formula I, where Ar² is phenyl, pyridinyl or pyrimidinyl, which may have one or two substituents which are selected, independently of one another, from C₁-C₆-alkyl, C₂-C₆-alkynyl, halogen, CN, haloalkyl,Oalkyl, NO₂, phenyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, cyclopentyl and cyclohexyl.
 10. A compound as claimed in claim 9 of the formula I, where the substituent(s) are selected, independently of one another, from C₁-C₆-alkyl, NO₂ and haloalkyl, in particular CF₃, CHF₂ and CF₂Cl.
 11. A pharmaceutical composition comprising at least one compound as claimed in any of claim 1, with or without physiologically acceptable vehicles and/or ancillary substances.
 12. A method for treating a disorder which responds to dopamine D₃ receptor antagonists or agonists which comprises treating the disorder with a compound of claim
 1. 